Burst Mass Research Articles

362-OR: The Role of Intraislet Glucagon in Pulsatile Insulin Secretion

Background: Type 2 diabetes (T2D) is characterised by the loss of pulsatile insulin secretion. We studied mice with β-cell specific loss of the glucagon receptor (GCGRflox/flox X Ins-1 cre) , to investigate the role of intra-islet glucagon signalling on pan-islet calcium oscillations and islet pulsatility. Methods: Frequently sampled intravenous glucose tolerance tests were conducted on GCGRKOβ-cells-/-and littermate controls. Crossing with GCaMP6f (STOP flox) animals allowed for β-cell specific expression of a fluorescent calcium indicator. These islets were functionally imaged in vitro and in vivo. Wild-type mice were transplanted with islets expressing GCaMP6f in β-cells into the anterior eye chamber and placed on a high fat diet. Half of the cohort received a glucagon analogue (GCG-analogue) for 40 days and the control group were fed to achieve weight matching. Calcium imaging was performed regularly during the development of hyperglycaemia and in response to GCG-analogue treatment. Results: GCGRKOβ-cells-/- mice had poorer glucose tolerance in an intraperitoneal glucose tolerance test (control 12.7mmol/L ±0.6 vs. GCGRKOβ-cells-/- 15.4mmol/L ±0.0 at 15 min, p=0.002) ; fasting glycaemia was not different to controls. In vitro, GCGRKOβ-cells-/- islets showed profound loss of synchronised calcium waves in response to glucose which is only partially rescued in vivo. First-phase insulin pulsatility on peripheral blood sampling (n=5) was significantly disordered in GCGRKOβ-cells-/- mice (burst mass GCGRKOβ-cells-/- 0.30 ±0.03 versus 0.84 ±0.23 for controls p=0.04) . Diet induced obesity and hyperglycaemia resulted in a loss of co-ordinated calcium waves in transplanted islets. This was reversed with GCG-analogue treatment, independently of weight-loss (n=8) . Conclusion: These data provide novel evidence for the role of intra-islet glucagon in sustaining synchronised calcium oscillations and support a possible therapeutic role for glucagonergic agents to restore the insulin pulsatility lost in T2D. Disclosure K.Suba: n/a. B.Jones: None. T.M.Tan: Consultant; Zihipp Ltd. B.Owen: None. D.J.Drucker: Consultant; Kallyope, Merck Sharp & Dohme Corp., Novo Nordisk, Pfizer Inc., Other Relationship; Eli Lilly and Company. S.Bloom: None. K.Murphy: None. V.Salem: None. Y.S.Patel: Employee; PerkinElmer. A.Roberts: None. J.V.Shrewsbury: None. S.Chen: None. R.Kwok: None. V.Kalogianni: None. X.Liu: None. G.A.Rutter: Advisory Panel; Sun Pharmaceutical Industries Ltd., Research Support; Sun Pharmaceutical Industries Ltd.

1787-P: Insulin Pulse Characteristics Do Not Alter Hepatic Glucose Metabolism and Insulin Action

Insulin is secreted into the portal vein in a pulsatile manner. Portal vein insulin concentrations directly and rapidly alter endogenous glucose production (EGP). Pulse frequency has been inversely correlated with hepatic insulin action in some, but not all, human studies. Indeed, increased pulse disorderliness, decreased secretory burst mass and decreased pulse frequency have been observed in type 2 diabetes, in aging and in obesity. In dogs, disruption of pulsatile insulin secretion is associated with defects in hepatic insulin action. As part of a series of experiments examining the mechanisms underlying prediabetes, we studied 29 nondiabetic subjects (BMI 28 ± 1 Kg/m2) on 2 occasions. On one occasion, EGP was measured using [3-3H]glucose after an overnight fast (14.2 ± 0.5μmol/kg/min) and during a euglycemic clamp (6.8 ± 1.1μmol/kg/min). The deuterated water method was used to estimate the contribution of gluconeogenesis to EGP. On a separate study day we utilized nonparametric stochastic deconvolution of frequently sampled peripheral C-peptide concentrations during fasting to reconstruct portal insulin secretion. In addition to measuring basal and pulsatile insulin secretion, we used Approximate Entropy (ApEn) to measure orderliness and a Fourier transform to measure the average and the dispersion of insulin pulse frequency. The gradient of Loge EGP vs. Loge insulin in each individual (-1.2 ± 0.5) was used as a measure of hepatic insulin action. Basal secretion (126 ± 8 pmol/min, R2=0.04), pulse amplitude (41 ± 38 pmol/min, R2=0.02), ApEn (1.14 ± 0.03, R2=0.01), pulse interval (5.7 ± 0.4 min, R2<0.01) and frequency dispersion (0.47 ± 0.01, R2<0.01) did not correlate (all p > 0.10) with hepatic insulin action. Suppression of gluconeogenesis by insulin also did not correlate with fasting insulin pulse characteristics. Overall, our data demonstrate that insulin pulse characteristics do not directly alter the sensitivity of EGP and gluconeogenesis to insulin in humans. Disclosure M.C. Laurenti: None. C. Dalla Man: Research Support; Self; Sanofi-Aventis Deutschland GmbH. R.T. Varghese: None. J. Jones: None. C. Barosa: None. R.A. Rizza: None. A. Matveyenko: None. G. De Nicolao: None. C. Cobelli: None. A. Vella: Advisory Panel; Self; vTv Therapeutics, Zealand Pharma A/S. Research Support; Self; Novo Nordisk A/S, Xeris Pharmaceuticals, Inc. Funding National Institutes of Health (DK78646, DK116231)

The star formation histories of z ∼ 1 post-starburst galaxies

ABSTRACT We present the star formation histories of 39 galaxies with high-quality rest-frame optical spectra at 0.5 < z < 1.3 selected to have strong Balmer absorption lines and/or Balmer break, and compare to a sample of spectroscopically selected quiescent galaxies at the same redshift. Photometric selection identifies a majority of objects that have clear evidence for a recent short-lived burst of star formation within the last 1.5 Gyr, i.e. ‘post-starburst’ galaxies, however we show that good quality continuum spectra are required to obtain physical parameters such as burst mass fraction and burst age. Dust attenuation appears to be the primary cause for misidentification of post-starburst galaxies, leading to contamination in spectroscopic samples where only the [O ii] emission line is available, as well as a small fraction of objects lost from photometric samples. The 31 confirmed post-starburst galaxies have formed 40–90 per cent of their stellar mass in the last 1–1.5 Gyr. We use the derived star formation histories to find that the post-starburst galaxies are visible photometrically for 0.5–1 Gyr. This allows us to update a previous analysis to suggest that 25–50 per cent of the growth of the red sequence at z ∼ 1 could be caused by a starburst followed by rapid quenching. We use the inferred maximum historical star formation rates of several 100–1000 M⊙ yr−1 and updated visibility times to confirm that sub-mm galaxies are likely progenitors of post-starburst galaxies. The short quenching time-scales of 100–200 Myr are consistent with cosmological hydrodynamic models in which rapid quenching is caused by the mechanical expulsion of gas due to an acive galactic neucleus.

Pulsatile Cortisol Feedback on ACTH Secretion Is Mediated by the Glucocorticoid Receptor and Modulated by Gender

Factors that regulate physiological feedback by pulses of glucocorticoids on the hypothalamic-pituitary unit are sparsely defined in humans in relation to gluco- or mineralocorticoid receptor pathways, gender, age, and the sex steroid milieu. The objective of the study was to test (the clinical hypothesis) that glucocorticoid (GR) and mineralocorticoid (MR) receptor-selective mechanisms differentially govern pulsatile cortisol-dependent negative feedback on ACTH output (by the hypothalamo-pituitary unit) in men and women studied under experimentally defined T and estradiol depletion and repletion, respectively. The study was conducted at the Mayo Center for Translational Science Activities. Healthy middle-aged men (n = 16) and women (n = 25) participated in the study. This was a randomized, prospective, double-blind, placebo- and saline-controlled study of pulsatile cortisol infusions in low cortisol-clamped volunteers with and without eplerenone (MR blocker) and mifepristone (GR blocker) administration under a low and normal T and estradiol clamp. During frequent sampling, a bolus of CRH-arginine vasopressin was infused to assess corticotrope responsiveness. Analytical Methods and Outcomes: Deconvolution and approximate entropy of ACTH profiles were measured. Infusion of cortisol (but not saline) pulses diminished ACTH secretion. The GR antagonist, mifepristone, interfered with negative feedback on both ACTH burst mass and secretion regularity. Eplerenone, an MR antagonist, exerted no detectable effect on the same parameters. Despite feedback imposition, CRH-arginine vasopressin-stimulated ACTH secretion was also increased by mifepristone and not by eplerenone. Withdrawal vs addback of sex steroids had no effect on ACTH secretion parameters. Nonetheless, ACTH secretion was greater (P = .006) and more regular (P = .004) in men than women. Pulsatile cortisol feedback on ACTH secretion in this paradigm is mediated by the glucocorticoid receptor, in part acting at the level of the pituitary, and influenced by sex.

Local starburst galaxies and their descendants

Despite strong interest in the starburst (hereafter SB) phenomenon, the concept remains ill-defined. We use a strict definition of SB to examine the statistical properties of local SB and post-starburst (hereafter PB) galaxies. We also seek relationships to active galaxies. Potential SB galaxies are selected from the SDSS DR7 and their stellar content is analysed. We apply an age dependent dust attenuation correction and derive star formation rates (SFR), ages and masses of the young and old populations. The photometric masses nicely agree with dynamical masses derived from the H-alpha emission line width. To select SB galaxies, we use the birthrate parameter b=SFR/<SFR>, requiring b>=3. The PB sample is selected from the citerion EW(Hdelta_abs)>=6 A. Only 1% of star-forming galaxies are found to be SB galaxies. They contribute 3-6% to the stellar production and are therefore unimportant for the local star formation activity. The median SB age is 70 Myr, roughly independent of mass. The b-parameter strongly depends on burst age. Values close to b=60 are found at ages ~10 Myr, while almost no SBs are found at ages >1 Gyr. The median baryonic burst mass fraction of sub-L* galaxies is 5%, decreasing slowly with mass. The median mass fraction of the recent burst in the PB sample is 5-10%. The age-mass distribution of the progenitors of the PBs is bimodal with a break at log(M)~10.6 above which the ages are doubled. The SB and PB luminosity functions (hereafter LFs) follow each other closely until M_r~-21, when AGNs begin to dominate. The PB LF continues to follow the AGN LF while SB loose significance. This suggests that the number of luminous SBs is underestimated by about one dex at high luminosities, due to large amounts of dust and/or AGN blending. It also indicates that the SB phase preceded the AGN phase. We also discuss the conditions for global gas outflow caused by stellar feedback.

Effects of Recombinant Human Leptin (Metreleptin) on Nocturnal Luteinizing Hormone Secretion in Lipodystrophy Patients

Background: Leptin replacement in patients with leptin gene mutations improves hypogonadotropic hypogonadism. The effects of leptin replacement on luteinizing hormone (LH) secretion in patients with lipodystrophy are unknown. Aim: We examined nocturnal LH secretory dynamics on and off exogenous leptin therapy using a 2-period, nonrandomized study that included leptin-naïve and leptin-treated subjects with lipodystrophy. Methods: In period 1 (5 days) the leptin-treated group (n = 4) continued leptin; leptin was then withdrawn for the next 14 days (period 2). Leptin-naïve subjects (n = 8) were studied without leptin in period 1 and with leptin replacement in period 2. LH secretory dynamics were assessed (23:00-07:00 h, sampling every 10 min, analyzed by multiparameter deconvolution algorithm) at the end of each period. Results: Mean (on vs. off: 5.0 ± 3.1 vs. 3.2 ± 1.3 IU/l, p = 0.04) and integrated LH concentrations (2,403 ± 1,495 vs. 1,534 ± 642 IU × l^-1 × min^-1, p = 0.04) were higher on leptin therapy. Leptin treatment increased burst mass (9.7± 15.4 vs. 7.0 ± 11.2 IU/l, p = 0.03) and tended to nonsignificantly increase LH burst frequency (0.77 ± 0.26 vs. 0.67 ± 0.24 h^-1, p = 0.08). Consequently, leptin therapy increased the pulsatile production rate (64 ± 101 vs. 57 ± 73 IU × l^-1 × 8 h^-1, p = 0.01). On leptin, testosterone (507 ± 286 vs. 360 ± 174 ng/dl, p = 0.09) and estradiol levels (74 ± 36 vs. 29 ± 24 pg/ml, p = 0.01) were higher in males and females, respectively. Conclusions: Leptin increases spontaneous nocturnal LH secretion in patients with lipodystrophy. This is consistent with rodent and in vitro studies showing a direct stimulatory effect (hypothalamic, pituitary or both) of leptin on LH secretion. These novel findings may explicate some of the salutary effects of leptin therapy on the hypothalamic-pituitary-gonadal axis in lipodystrophy.

Effects of 12 weeks high dose vitamin D3 treatment on insulin sensitivity, beta cell function, and metabolic markers in patients with type 2 diabetes and vitamin D insufficiency – a double-blind, randomized, placebo-controlled trial

ObjectivesVitamin D insufficiency is common in subjects with type 2 diabetes. Observational studies suggest that vitamin D plays a role in the pathogenesis of type 2 diabetes. However, results of intervention studies have been inconsistent. We investigated the effects of improving vitamin D status on insulin sensitivity, insulin secretion, and inflammatory markers in patients with type 2 diabetes. Materials/methodsA double blind, randomized, placebo controlled trial was conducted. Sixteen patients with type 2 diabetes and hypovitaminosis D were recruited. Eight patients received colecalciferol and (280μg daily for 2weeks, 140μg daily for 10weeks) and 8 patients received identical placebo tablets for 12weeks. Before and after intervention, patients underwent IVGTT, hyperinsulinemic euglycemic clamp, assessment of baseline high-frequency insulin pulsatility, glucose-entrained insulin pulsatility, DXA scans, 24-hour-ambulatory blood pressure monitorings, and fasting blood samples. ResultsSerum-25(OH) vitamin D and serum-1,25(OH)2 vitamin D increased significantly after 12weeks in the intervention group (p=0.01, p=0.004). Serum-25(OH) vitamin D was also significantly higher in the vitamin D group compared to the placebo group (p=0.02) after intervention. Although no significant changes in insulin sensitivity, inflammation, blood pressure, lipid profile, or HbA1c were found, we observed borderline (p between 0.05 and 0.10) improvements of insulin secretion, in terms of c-peptide levels, first phase incremental AUC insulin and insulin secretory burst mass. ConclusionsImprovement in vitamin D status does not improve insulin resistance, blood pressure, inflammation or HbA1c, but might increase insulin secretion in patients with established type 2 diabetes.

Quantitative constraints on starburst cycles in galaxies with stellar masses in the range 108-1010 M

We have used 4000 u break and HA indices in combination with SFR/M∗ derived from emission line flux measurements, to constrain the recent star formation histories of galaxies with stellar masses in the range 10 8 − 10 10 M⊙. The fraction of the total SFR density in galaxies with ongoing bursts is a strong function of stellar mass, de- clining from 0.85 at a stellar mass of 10 8 M⊙ to 0.25 for galaxies with M∗ ∼ 10 10 M⊙. Low mass galaxies are not all young. The distribution of half mass formation times for galaxies with stellar masses less than 10 9 M⊙ is broad, spanning the range 1-10 Gyr. The peak-to-trough variation in star formation rate among the bursting population ranges lies in the range 10-25. In low mass galaxies, the average duration of the burst bursts is comparable to the dynamical time of the galaxy. Galaxy structure is corre- lated with estimated burst mass fraction, but in different ways in low and high mass galaxies. High mass galaxies with large burst mass fractions are more centrally concen- trated, indicating that bulge formation is at work. In low mass galaxies, stellar surface densities µ∗ decrease as a function of Fburst. These results are in good agreement with the observational predictions of Teyssier et al (2013) and lend further credence to the idea that the cuspy halo problem can be solved by energy input from multiple star- bursts over the lifetime of the galaxy. We note that there is no compelling evidence for IMF variations in the population of star-forming galaxies in the local Universe.

Continuous positive airway pressure increases pulsatile growth hormone secretion and circulating insulin-like growth factor-1 in a time-dependent manner in men with obstructive sleep apnea: a randomized sham-controlled study.

To assess the time-dependent effect of continuous positive airway pressure (CPAP), on insulin-like growth factor-1 (IGF-1), IGF binding proteins (IGFBPs) and pulsatile growth hormone (GH) secretion. A randomized, double-blind, sham-controlled, parallel group study. Sixty-five middle-aged men with moderate to severe obstructive sleep apnea. Active (n = 34) or sham (n = 31) CPAP for 12 weeks, followed by 12 weeks of active CPAP (n = 65). Fasting morning IGF-1, IGFBP-3, and IGFBP-1 blood levels at 0, 6, 12, and 24 weeks. Overnight GH secretion was calculated by mathematical deconvolution of serial GH measurements from serum samples collected every 10 min (22:00-06:00) during simultaneous polysomnography in a subset of 18 men (active n = 11, sham n = 7) at week 12. Active, compared with sham, CPAP increased IGF-1 at 12 weeks (P = 0.006), but not at 6 weeks (P = 0.44). Changes in IGFBP-3 and IGFBP-1 were not different between groups at 6 or 12 weeks (all P ≥ 0.15). At week 24, there was a further increase in IGF-1 and a decrease in IGFBP-1 in the pooled group (P = 0.0001 and 0.046, respectively). In the subset, total (P = 0.001) and pulsatile (P = 0.002) GH secretion, mean GH concentration (P = 0.002), mass of GH secreted per pulse (P = 0.01) and pulse frequency (P = 0.04) were all higher after 12 weeks of CPAP compared with sham. Basal secretion, interpulse regularity, and GH regularity were not different between groups (all P > 0.11). Twelve weeks, but not 6 weeks, of CPAP increases IGF-1, with a further increase after 24 weeks. Total and pulsatile GH secretion, secretory burst mass and pulse frequency are also increased by 12 weeks. CPAP improves specific elements of the GH/IGF-1 axis in a time-dependent manner. Australia New Zealand Clinical Trials Network, www.anzctr.org.au, number ACTRN12608000301369.

Reduced nocturnal ACTH-driven cortisol secretion during critical illness

Recently, during critical illness, cortisol metabolism was found to be reduced. We hypothesize that such reduced cortisol breakdown may suppress pulsatile ACTH and cortisol secretion via feedback inhibition. To test this hypothesis, nocturnal ACTH and cortisol secretory profiles were constructed by deconvolution analysis from plasma concentration time series in 40 matched critically ill patients and eight healthy controls, excluding diseases or drugs that affect the hypothalamic-pituitary-adrenal axis. Blood was sampled every 10 min between 2100 and 0600 to quantify plasma concentrations of ACTH and (free) cortisol. Approximate entropy, an estimation of process irregularity, cross-approximate entropy, a measure of ACTH-cortisol asynchrony, and ACTH-cortisol dose-response relationships were calculated. Total and free plasma cortisol concentrations were higher at all times in patients than in controls (all P < 0.04). Pulsatile cortisol secretion was 54% lower in patients than in controls (P = 0.005), explained by reduced cortisol burst mass (P = 0.03), whereas cortisol pulse frequency (P = 0.35) and nonpulsatile cortisol secretion (P = 0.80) were unaltered. Pulsatile ACTH secretion was 31% lower in patients than in controls (P = 0.03), again explained by a lower ACTH burst mass (P = 0.02), whereas ACTH pulse frequency (P = 0.50) and nonpulsatile ACTH secretion (P = 0.80) were unchanged. ACTH-cortisol dose response estimates were similar in patients and controls. ACTH and cortisol approximate entropy were higher in patients (P ≤ 0.03), as was ACTH-cortisol cross-approximate entropy (P ≤ 0.001). We conclude that hypercortisolism during critical illness coincided with suppressed pulsatile ACTH and cortisol secretion and a normal ACTH-cortisol dose response. Increased irregularity and asynchrony of the ACTH and cortisol time series supported non-ACTH-dependent mechanisms driving hypercortisolism during critical illness.

Preparation, Characterization and &lt;i&gt;In Vitro&lt;/i&gt; Release Kinetics of Vancomycin Carried β-TCP/Chitosan Composite Microspheres Used as Bone Tissue Engineering Scaffolds

A novel microsphere scaffolds composed of chitosan and β-TCP containing vancomycin was designed and prepared. The β-TCP/chitosan composite microspheres were prepared by solid-in-water-in-oil (s/w/o) emulsion cross-linking method with or without pre-cross-linking process. The mode of vancomycin maintaining in the β-TCP/chitosan composite microspheres was detected by Fourier transform infrared spectroscopy (FTIR). The in vitro release curve of vancomycin in simulated body fluid (SBF) was estimated. The results revealed that the pre-cross-linking prepared microspheres possessed higher loading efficiency (LE) and encapsulation efficiency (EE) especially decreasing the previous burst mass of vancomycin in incipient release. These composite microspheres got excellent sphere and well surface roughness in morphology. Vancomycin was encapsulated in composite microspheres through absorption and cross-linking. While in-vitro release curves illustrated that vancomycin release depond on diffusing firstly and then on the degradation ratio later. The microspheres loading with vancomycin would be to restore bone defect, meanwhile to inhibit bacterium proliferation. These bioactive, degradable composite microspheres have potential applications in 3D tissue engineering of bone and other tissues in vitro and in vivo.

From star-forming spirals to passive spheroids: integral field spectroscopy of E+A galaxies

We present three-dimensional spectroscopy of 11 E+A galaxies at z= 0.06–0.12. These galaxies were selected for their strong Hδ absorption but weak (or non-existent) [O ii] λ3727 and Hα emission. This selection suggests that a recent burst of star formation was triggered but subsequently abruptly ended. We probe the spatial and spectral properties of both the young (≲1 Gyr) and old (≳few Gyr) stellar populations. Using the Hδ equivalent widths we estimate that the burst masses must have been at least 10 per cent by mass (Mburst≳ 1010 M⊙), which is also consistent with the star formation history inferred from the broad-band spectral energy distributions. On average the A stars cover ∼33 per cent of the galaxy image, extending over 2–15 kpc2, indicating that the characteristic E+A signature is a property of the galaxy as a whole and not due to a heterogeneous mixture of populations. In approximately half of the sample, we find that the A stars, nebular emission and continuum emission are not co-located, suggesting that the newest stars are forming in a different place than those that formed ≲1 Gyr ago, and that recent star formation has occurred in regions distinct from the oldest stellar populations. At least 10 of the galaxies (91 per cent) have dynamics that class them as ‘fast rotators’ with magnitudes, v/σ, λR and bulge-to-total (B/T) ratio comparable to local, representative ellipticals and S0s. We also find a correlation between the spatial extent of the A stars and the dynamical state of the galaxy such that the fastest rotators tend to have the most compact A star populations, providing new constraints on models that aim to explain the transformation of later type galaxies into early types. Finally, we show that there are no obvious differences between the line extents and kinematics of E+A galaxies detected in the radio (active galactic nucleus, AGN) compared to non-radio sources, suggesting that AGN feedback does not play a dramatic role in defining their properties, and/or that its effects are short.

Loss of Inverse Relationship Between Pulsatile Insulin and Glucagon Secretion in Patients With Type 2 Diabetes

OBJECTIVEIn patients with type 2 diabetes, glucagon levels are often increased. Furthermore, pulsatile secretion of insulin is disturbed in such patients. Whether pulsatile glucagon secretion is altered in type 2 diabetes is not known.RESEARCH DESIGN AND METHODSTwelve patients with type 2 diabetes and 13 nondiabetic individuals were examined in the fasting state and after mixed meal ingestion. Deconvolution analyses were performed on insulin and glucagon concentration time series sampled at 1-min intervals.RESULTSBoth insulin and glucagon were secreted in distinct pulses, occurring at ∼5-min intervals. In patients with diabetes, postprandial insulin pulse mass was reduced by 74% (P < 0.001). Glucagon concentrations were increased in the patients during fasting and after meal ingestion (P < 0.05), specifically through an increased glucagon pulse mass (P < 0.01). In healthy subjects, the increase in postprandial insulin levels was inversely related to respective glucagon levels (P < 0.05). This relationship was absent in the fasting state and in patients with diabetes.CONCLUSIONSGlucagon and insulin are secreted in a coordinated, pulsatile manner. A plausible model is that the postprandial increase in insulin burst mass represses the corresponding glucagon pulses. Disruption of the insulin–glucagon interaction in patients with type 2 diabetes could potentially contribute to hyperglucagonemia.

Kisspeptin-10 Is a Potent Stimulator of LH and Increases Pulse Frequency in Men

Kisspeptins stimulate GnRH and thus gonadotropin secretion. Kisspeptin-10 is the minimal kisspeptin sequence with full intrinsic bioactivity, but it has not been studied in man. We investigated our hypothesis that kisspeptin-10 increases GnRH and thus LH pulse frequency. The dose response of kisspeptin-10 was investigated by administering iv bolus doses (0.01-3.0 μg/kg) and vehicle to healthy men. Effects on LH pulse frequency and size were determined by deconvolution analysis during infusion of kisspeptin-10 for up to 22.5 h. Intravenous bolus kisspeptin-10 resulted in a rapid and dose-dependent rise in serum LH concentration, with maximal stimulation at 1 μg/kg (4.1 ± 0.4 to 12.4 ± 1.7 IU/liter at 30 min, P < 0.001, n = 6). Administration of 3 μg/kg elicited a reduced response vs. 1 μg/kg (P < 0.05). Infusion of kisspeptin-10 at 4 μg/kg · h for 22.5 h elicited an increase in LH from a mean of 5.4 ± 0.7 to 20.8 ± 4.9 IU/liter (n = 4; P < 0.05) and serum testosterone increased from 16.6 ± 2.4 to 24.0 ± 2.5 nmol/liter (P < 0.001). LH pulses were obscured at this high rate of secretion, but a lower dose infusion of kisspeptin-10 (1.5 μg/kg · h) increased mean LH from 5.2 ± 0.8 to 14.1 ± 1.7 IU/liter (n = 4; P < 0.01) and increased LH pulse frequency from 0.7 ± 0.1 to 1.0 ± 0.2 pulses/h (P < 0.05) and secretory burst mass from 3.9 ± 0.4 to 12.8 ± 2.6 IU/liter (P < 0.05). Kisspeptin-10 boluses potently evoke LH secretion in men, and continuous infusion increases testosterone, LH pulse frequency, and pulse size. Kisspeptin analogues have therapeutic potential as regulators of LH and thus testosterone secretion.

A new empirical method to infer the starburst history of the Universe from local galaxy properties

The centers of bulges are formed dissipationally via gas inflows over short timescales: the 'starburst' mode of star formation (SF). Recent work has shown that detailed observations can be used to separate the stellar mass profile of these 'burst relic' components in local systems. Together with the assumption that some Kennicutt-Schmidt law holds, and that the burst was indeed a dissipational gas-rich event, we show that the observed profiles can be inverted to obtain the time and space-dependent SF history of each burst. Performing this with a large sample of well-studied spheroids, we show that the implied bursts scale in magnitude, mass, peak SFR, and spatial extent with galaxy mass in simple manner, and provide fits to these correlations. Burst masses are ~10% the total spheroid mass; timescales a mass-independent ~10^8 yr; peak SFR ~M_burst/t_burst; and they decay in power-law fashion ~t^-2.4. Sizes are ~0.1 R_e(spheroid), but grow with time. Combined with measurements of the nuclear stellar population ages of these systems (i.e. burst times), it is possible to re-construct the burst contribution to the distribution of SFRs and IR luminosity functions at all redshifts. The burst LF agrees well with observed IR LFs at the brightest luminosities, at z=0-2. At low-L, bursts are always unimportant; the transition to their importance increases from ULIRG luminosities at z~0 to HyLIRG luminosities at z~2. At all redshifts, bursts are a small fraction (~5-10%) of the total SFR density. We discuss possible implications of tension between maximum relic stellar mass densities in massive systems, and estimated number counts of brightest sub-millimeter galaxies.

The effect of caloric restriction interventions on growth hormone secretion in nonobese men and women

Lifespan in rodents is prolonged by caloric restriction (CR) and by mutations affecting the somatotropic axis. It is not known if CR can alter the age-associated decline in growth hormone (GH), insulin-like growth factor (IGF)-1 and GH secretion. To evaluate the effect of CR on GH secretory dynamics; forty-three young (36.8 +/- 1.0 years), overweight (BMI 27.8 +/- 0.7) men (n = 20) and women (n = 23) were randomized into four groups; control = 100% of energy requirements; CR = 25% caloric restriction; CR + EX = 12.5% CR + 12.5% increase in energy expenditure by structured exercise; LCD = low calorie diet until 15% weight reduction followed by weight maintenance. At baseline and after 6 months, body composition (DXA), abdominal visceral fat (CT) 11 h GH secretion (blood sampling every 10 min for 11 h; 21:00-08:00 hours) and deconvolution analysis were measured. After 6 months, weight (control: -1 +/- 1%, CR: -10 +/- 1%, CR + EX: -10 +/- 1%, LCD: -14 +/- 1%), fat mass (control: -2 +/- 3%, CR: -24 +/- 3%, CR + EX: -25 +/- 3%, LCD: -31 +/- 2%) and visceral fat (control: -2 +/- 4%, CR: -28 +/- 4%, CR + EX: -27 +/- 3%, LCD: -36 +/- 2%) were significantly (P < 0.001) reduced in the three intervention groups compared to control. Mean 11 h GH concentrations were not changed in CR or control but increased in CR + EX (P < 0.0001) and LCD (P < 0.0001) because of increased secretory burst mass (CR + EX: 34 +/- 13%, LCD: 27 +/- 22%, P < 0.05) and amplitude (CR + EX: 34 +/- 14%, LCD: 30 +/- 20%, P < 0.05) but not to changes in secretory burst frequency or GH half-life. Fasting ghrelin was significantly increased from baseline in all three intervention groups; however, total IGF-1 concentrations were increased only in CR + EX (10 +/- 7%, P < 0.05) and LCD (19 +/- 4%, P < 0.001). A 25% CR diet for 6 months does not change GH, GH secretion or IGF-1 in nonobese men and women.

Thyrotropin Secretion in Mild and Severe Primary Hypothyroidism Is Distinguished by Amplified Burst Mass and Basal Secretion with Increased Spikiness and Approximate Entropy

Twenty-four-hour TSH secretion profiles in primary hypothyroidism have been analyzed with methods no longer in use. The insights afforded by earlier methods are limited. We studied TSH secretion in patients with primary hypothyroidism (eight patients with severe and eight patients with mild hypothyroidism) with up-to-date analytical tools and compared the results with outcomes in 38 healthy controls. Patients and controls underwent a 24-h study with 10-min blood sampling. TSH data were analyzed with a newly developed automated deconvolution program, approximate entropy, spikiness assessment, and cosinor regression. Both basal and pulsatile TSH secretion rates were increased in hypothyroid patients, the latter by increased burst mass with unchanged frequency. Secretory regularity (approximate entropy) was diminished, and spikiness was increased only in patients with severe hypothyroidism. A diurnal TSH rhythm was present in all but two patients, although with an earlier acrophase in severe hypothyroidism. The estimated slow component of the TSH half-life was shortened in all patients. Increased TSH concentrations in hypothyroidism are mediated by amplification of basal secretion and burst size. Secretory abnormalities quantitated by approximate entropy and spikiness were only present in patients with severe disease and thus are possibly related to the increased thyrotrope cell mass.

Testosterone Supplementation in Older Men Restrains Insulin-Like Growth Factor’s Dose-Dependent Feedback Inhibition of Pulsatile Growth Hormone Secretion

Pulsatile GH secretion declines in older men. The causal mechanisms are unknown. Candidates include deficient feedforward (stimulation) by endogenous secretagogues and excessive feedback (inhibition) by GH or IGF-I due to age and/or relative hypoandrogenemia. Testosterone (T) supplementation in healthy older men will restrain negative feedback by systemic concentrations of IGF-I. Twenty-four healthy men (ages, 50 to 75 yr; body mass index, 24 to 30 kg/m(2)) participated in the study. We performed a prospectively randomized, double-blind, placebo-controlled assessment of the impact of pharmacological T supplementation on GH responses to randomly ordered separate-day injections of recombinant human IGF-I doses of 0, 1.0, 1.5, and 2.0 mg/m(2). Deconvolution and approximate entropy analyses of pulsatile, basal, and entropic (pattern-sensitive) modes of GH secretion were conducted. Recombinant human IGF-I injections 1) elevated mean and peak serum IGF-I concentrations dose-dependently (both P < 0.001); 2) suppressed pulsatile GH secretion (P = 0.003), burst mass (P = 0.025), burst number (P = 0.005), interpulse variability (P = 0.032), and basal GH secretion (P = 0.009); and 3) increased secretory pattern regularity (P = 0.020). T administration did not alter experimentally controlled IGF-I concentrations, but it elevated mean GH concentrations (P = 0.015) and stimulated pulsatile GH secretion (frequency P = 0.037, mass per burst P = 0.038). Compared with placebo, T attenuated exogenous IGF-I's inhibition of GH secretory-burst mass (P < 0.038) without restoring pulse number, basal secretion, or pattern regularity. The capability of systemic T to mute IGF-I feedback on pulsatile GH secretion suggests a novel mechanism for augmenting GH production.

On high-frequency insulin oscillations

Insulin is released in a pulsatile manner, which results in oscillatory concentrations in blood. The oscillatory secretion improves release control and enhances the hormonal action. Insulin oscillates with a slow ultradian periodicity (∼140 min) and a high-frequency periodicity (∼6–10 min). Only the latter is reviewed in this article. At least 75% of the insulin secretion is released in a pulsatile manner. Individuals prone to developing diabetes or with overt type 2 diabetes are characterized by irregular oscillations of plasma insulin. Many factors have impact on insulin pulsatility such as age, insulin resistance and glycemic level. In addition, tiny glucose oscillations are capable of entraining insulin oscillations in healthy people in contrast to type 2 diabetic individuals emphasizing a profound disruption of the beta-cells in type 2 diabetes to sense or respond to physiological glucose excursions. A crucial question is how ∼1,000,000 islets, each containing from a few to several thousand beta-cells, can be coordinated to secrete insulin in a pulsatile manner. This is blatantly a very complex operation to control involving an intra-pancreatic neural network, an intra-islet communication and metabolic oscillations in the beta-cell itself. Overnight beta-cell rest, e.g. during somatostatin administration, improves the disordered pulsatile insulin secretion in type 2 diabetes. Acute as well as long-term administration of sulphonylureas (SU) leads to substantial amplification (∼50%) of the pulsatile insulin secretion in type 2 diabetes. This is probably cardinal in terms of governing the hepatic glucose release in type 2 diabetes. Whether sulfonylureas also improve the ability of the beta-cells to sense glucose fluctuations remains to be explored. Thiazolidinediones reduce the pulsatile insulin secretion without affecting regularity, but appear to improve the ability of the beta-cell to be entrained by small glucose excursions. Finally, similar to SUs, the incretin hormone GLP-1 also results in an augmented pulsatile burst mass in both healthy and diabetic individuals, in the latter group, however, without influencing the disorderliness of pulses. This review will briefly describe the high-frequency insulin pulsatility during physiologic and pathophysiologic conditions as well as the influence of some hypoglycemic compounds on the insulin oscillations.

Fasting Insulin Pulsatile Secretion in Lean Women with Polycystic Ovary Syndrome

The aim of our study was to evaluate rapid insulin pulses and insulin secretion regularity in fasting state in lean women with polycystic ovary syndrome (PCOS) in comparison to lean healthy women. PCOS (n=8) and controls (n=7) underwent every minute blood sampling for 60 min. Insulin pulsatility was assessed by deconvolution and insulin secretion regularity by approximate entropy methodology. PCOS had higher testosterone (p<0.02), prolactin (p<0.05) and lower sex hormone binding globulin (SHBG) (p<0.0006) levels than controls. Approximate entropy, insulin pulse frequency, mass, amplitude and interpulse interval did not differ between PCOS and controls. PCOS had broader insulin peaks determined by a common half-duration (p<0.07). Burst mass correlated positively with testosterone (p<0.05) and negatively with SHBG (p 0.0004) and common half-duration correlated positively with prolactin (p<0.008) and cortisol levels (p<0.03). Approximate entropy positively correlated with BMI (p<0.04) and prolactin (p<0.03). Lean PCOS patients tended to have broader insulin peaks in comparison to healthy controls. Prolactin, androgens and cortisol might participate in alteration of insulin secretion in PCOS-affected women. Body weight and prolactin levels could influence insulin secretion regularity.