带时间延迟的Cohen-Grossberg神经网络全局鲁棒稳定性的一个结果（英文）

在本文中,我们讨论了一类带时间延迟的Cohen-Grossberg神经网络,并研究了这个系统平衡点的全局鲁棒稳定性。利用Lyapunov函数,我们得出了全局鲁棒收敛性的几个充分条件。这些条件以线性矩阵不等式（LMI）的形式表达。因此,从计算的角度出发他们是高效的。另外,这些条件不依赖于时间延迟和神经网络的激发函数。     

变时延神经网络的全局指数稳定性及收敛性

利用Lyapunov泛函方法和线性矩阵不等式（LMI）技术,通过引入一系列参数,给出全局指数稳定的平衡点的判别条件和时延的最大上界和神经网络的收敛速度,所得结果较之一些文献中的结果简单、实用并且对于具体设计带时延神经网络有重要的指导意义.最后,通过实例表明给出的判定条件是有效、可行的.     

Assessment of beta-cell function in humans, simultaneously with insulin sensitivity and hepatic extraction, from intravenous and oral glucose tests

Assessment of insulin secretion in humans under physiological conditions has been a challenge because of its complex interplay with insulin action and hepatic insulin extraction. The possibility of simultaneously assessing beta-cell function, insulin sensitivity, and hepatic insulin extraction under physiological conditions using a simple protocol is appealing, since it has the potential to provide novel insights regarding the regulation of fasting and postprandial glucose metabolism in diabetic and nondiabetic humans. In this Perspective, we review data indicating that an oral glucose tolerance test (OGTT) or a meal test is able to accomplish this goal when interpreted with the oral beta-cell minimal model. We begin by using the well-established intravenous minimal model to highlight how the oral minimal model was developed and how the oral assessment parallels that of an intravenous glucose tolerance test (IVGTT). We also point out the unique aspects of both approaches in relation to their ability to assess different aspects of the beta-cell secretory cascade. We review the ability of the oral model to concurrently measure insulin sensitivity and hepatic insulin extraction, thereby enabling it to quantitatively portray the complex relationship among beta-cell function, hepatic insulin extraction, and insulin action. In addition, data from 204 individuals (54 young and 159 elderly) who underwent both IVGTT and meal tolerance tests are used to illustrate how these different approaches provide complementary but differing insights regarding the regulation of beta-cell function in humans.     

Glucose metabolism in the basal state and during a two-hour glucose infusion in low insulin responders and control subjects

Glucose metabolism was studied in eight low insulin responders to glucose and eight controls using a primed-constant tracer infusion technique. The tracer was 3-3H-glucose. The former group demonstrated a lower IVGTT than the controls, although the K-values were well within the normal range. They also attained higher blood glucose levels during iv administration of high and low glucose loads. Glucose turnover studies revealed normal hepatic glucose production, normal total glucose uptake and normal metabolic clearance of glucose in the low responders as a group. The findings suggest normal sensitivity to insulin in these subjects, and imply that the low insulin response is the sole mediator of the observed lowering in IVGTT.     

Changes in the serum composition of free-fatty acids during an intravenous glucose tolerance test

Recent studies suggest that measuring the free-fatty acids (FFA) during an intravenous glucose tolerance test (IVGTT) may provide information about the metabolic associations between serum FFA and carbohydrate and insulin metabolism. We evaluated the FFA profile during an IVGTT and determined whether this test changes the composition and concentration of FFA. An IVGTT was given to 38 severely obese persons before and 7 months after undergoing bariatric surgery and also to 12 healthy, nonobese persons. The concentration and composition of the FFA were studied at different times during the test. The concentration of FFA fell significantly faster during the IVGTT in the controls and in the severely obese persons with normal-fasting glucose (NFG) than in the severely obese persons with impaired-fasting glucose (IFG) or type 2 diabetes mellitus (T2DM) (P < 0.05). Significant differences were found in the time to minimum serum concentrations of FFA (control = NFG < IFG < T2DM) (P < 0.001). These variables improved after bariatric surgery in the three groups. The percentage of monounsaturated and n-6 polyunsaturated FFA in the control subjects and in the obese persons, both before and after surgery, decreased significantly during the IVGTT. In conclusion, during an IVGTT, severely obese persons with IFG or T2DM experienced a lower fall in the FFA than the severely obese persons with NFG and the controls, becoming normal after bariatric surgery.     

Sex-specific effects of placental restriction on components of the metabolic syndrome in young adult sheep

Prenatal and early postnatal life experiences, reflected by size at birth and postnatal catch-up growth, contribute to the risk of developing the metabolic syndrome in adulthood, but their relative importance is unclear. Therefore, we determined the effects of restricted placental and fetal growth on components of the metabolic syndrome in young adult sheep and the relationships of the latter to size at birth and early postnatal growth. Fasting plasma metabolites, glucose tolerance (by intravenous glucose tolerance test, IVGTT), insulin secretion and sensitivity, and resting blood pressure were measured in 22 control and 20 placentally restricted (PR) 1-yr-old sheep. In male sheep, PR increased the initial rise in glucose during an IVGTT and reduced diastolic blood pressure, and small size at birth independently predicted reduced adult size, glucose tolerance, and fasting plasma insulin and insulin disposition of glucose metabolism but increased insulin disposition of circulating FFAs. Also in males, high fractional growth rates in early postnatal life independently predicted impaired early glucose clearance during an IVGTT. In female animals, PR increased insulin sensitivity of glucose metabolism and reduced fasting plasma FFAs, and thinness at birth predicted increased adult size, fasting blood glucose, and pulse pressure. In conclusion, PR and small size at birth are associated with more components of the metabolic syndrome in adult male than in adult female sheep, with few independent effects of early postnatal growth. These sex differences in the onset and extent of adverse metabolic consequences after prenatal restraint in the sheep are consistent with observations in humans.     

Establishment of a Refined Oral Glucose Tolerance Test in Pigs,and Assessment of Insulin,Glucagon and Glucagon-Like Peptide-1 Responses

Diabetes mellitus is increasing worldwide and reliable animal models are important for progression of the research field. The pig is a commonly used large animal model in diabetes research and the present study aimed to refine a model for oral glucose tolerance test (OGTT) in young growing pigs, as well as describing intravenous glucose tolerance test (IVGTT) in the same age group. The refined porcine OGTT will reflect that used in children and adolescents. Eighteen pigs were obtained one week after weaning and trained for two weeks to bottle-feed glucose solution, mimicking the human OGTT. The pigs subsequently underwent OGTT (1.75 g/kg BW) and IVGTT (0.5 g/kg BW). Blood samples were collected from indwelling vein catheters for measurements of glucose and the diabetes related hormones insulin, glucagon and active glucagon-like peptide-1. The study confirmed that pigs can be trained to bottle-feed glucose dissolved in water and thereby undergo an OGTT more similar to the human standard OGTT than previously described methods in pigs. With the refined method for OGTT, oral intake only consists of glucose and water, which is an advantage over previously described methods in pigs where glucose is given together with feed which will affect glucose absorption. Patterns of hormonal secretion in response to oral and intravenous glucose were similar to those in humans; however, the pigs were more glucose tolerant with lower insulin levels than humans. In translational medicine, this refined OGTT and IVGTT methods provide important tools in diabetes research when pigs are used as models for children and adolescents in diabetes research.     

Postnatal ontogeny of glucose homeostasis and insulin action in sheep

Glucose tolerance declines with maturation and aging in several species, but the time of onset and extent of changes in insulin sensitivity and insulin secretion and their contribution to changes in glucose tolerance are unclear. We therefore determined the effect of maturation on glucose tolerance, insulin secretion, and insulin sensitivity in a longitudinal study of male and female sheep from preweaning to adulthood, and whether these measures were related across age. Glucose tolerance was assessed by intravenous glucose tolerance test (IVGTT, 0.25 g glucose/kg), insulin secretion as the integrated insulin concentration during IVGTT, and insulin sensitivity by hyperinsulinemic-euglycemic clamp (2 mU insulin.kg(-1).min(-1)). Glucose tolerance, relative insulin secretion, and insulin sensitivity each decreased with age (P < 0.001). The disposition index, the product of insulin sensitivity, and various measures of insulin secretion during fasting or IVGTT also decreased with age (P < 0.001). Glucose tolerance in young adult sheep was independently predicted by insulin sensitivity (P = 0.012) and by insulin secretion relative to integrated glucose during IVGTT (P = 0.005). Relative insulin secretion before weaning was correlated positively with that in the adult (P = 0.023), whereas glucose tolerance, insulin sensitivity, and disposition indexes in the adult did not correlate with those at earlier ages. We conclude that glucose tolerance declines between the first month of life and early adulthood in the sheep, reflecting decreasing insulin sensitivity and absence of compensatory insulin secretion. Nevertheless, the capacity for insulin secretion in the adult reflects that early in life, suggesting that it is determined genetically or by persistent influences of the perinatal environment.     

Coupling of insulin receptors to glucose transport: a temperature-dependent time lag in activation of glucose transport.

We have studied the ability of occupied insulin receptors to activate (or couple to) the glucose transport system in isolated rat adipocytes. Maximal insulin action is seen when only a small proportion (<10%) of the receptors is occupied, and this fraction can be rapidly filled (<5 s) at an insulin concentration of 100 ng/ml. Additionally, control studies show that when the extracellular glucose concentration is tripled, the rate of transport triples within 10 s, indicating that changes in transport activity can be observed nearly instantaneously. Therefore, when cells are exposed to a high insulin concentration (100 ng/ml), any delay in the onset of insulin action beyond this time must be due to the time required for coupling of occupied insulin receptors to the glucose transport system. At 24 °C there is a lag of at least 200 s after insulin addition before a significant stimulation of 2-deoxyglucose transport is seen. The length of this lag phase is temperature dependent, decreasing to 45 s at 37 °C. An Arrhenius plot of the coupling lag is linear, with an activation energy of 25 kcal/mol. After the delay in the onset of initial transport activation the full response appears in a gradual manner, requiring 20 min at 24 °C to attain maximal stimulation. The time required for the full insulin response to appear is also temperature dependent, decreasing to 5 min at 37 °C. Similar results were obtained for the kinetics of insulin activation of 3-O-methyl glucose transport. Thus, the coupling of insulin receptors to the glucose transport system can be divided into two components: an initial absolute time lag followed by a gradual incremental process before the maximal, or full, effect of insulin is achieved. In conclusion, (1) there is an absolute delay in the onset of the insulin's initial action on glucose transport, (2) after an initial delay, activation of transport proceeds in a gradual manner, and (3) the coupling process between insulin receptors and the glucose transport system is temperature dependent and can be described by a linear Arrhenius plot. This suggests that the rate of activation is not limited by membrane fluidity.     

Computed insulin profiles for normalization of glycemia in diabetic patients

The objective of this preliminary study was to develop a new quantitative method of setting the initial insulin infusion patterns in treatment of diabetic patients. The method is based upon the mathematical estimation of the insulin profile required to maintain the glucose level within the normal range after glucose loading in diabetic patients. Using our previously developed equivalent circuit model of glucose kinetics and the reported data of an intravenous glucose tolerance test (IVGTT) in two groups of normal and diabetic patients, two important physiological parameters of the model (the peripheral tissue's insulin resistivity and the hepatic sensitivity to glucose level) were computed for two clinical groups. Then the insulin profile was obtained by computing the plasma insulin concentrations required to keep the total glucose utilization rate of the tissue and the liver in the diabetic group equal to that of the normal group. The simulation result indicated that the computed insulin profile produced a plasma glucose profile which was more closely matched to the normal group's glucose profile than with the case of emulating the normal group's insulin profile in the diabetic group.     

Epinephrine effects on insulin-glucose dynamics: the labeled IVGTT two-compartment minimal model approach

The hyperglycemic effects of epinephrine (Epi) are established; however, the modulation of Epi-stimulated endogenous glucose production (EGP) by glucose and insulin in vivo in humans is less clear. Our aim was to determine the effect of exogenously increased plasma Epi concentrations on insulin and glucose dynamics. In six normal control subjects, we used the labeled intravenous glucose tolerance test (IVGTT) interpreted with the two-compartment minimal model, which provides not only glucose effectiveness (S(G)(2*)), insulin sensitivity (S(I)(2*)), and plasma clearance rate (PCR) at basal state, but also the time course of EGP. Subjects were randomly studied during either saline or Epi infusion (1.5 microg/min). Exogenous Epi infusion increased plasma Epi concentration to a mean value of 2,034 +/- 138 pmol/l. During the stable-label IVGTT, plasma glucose, tracer glucose, and insulin concentrations were significantly higher in the Epi study. The hormone caused a significant (P < 0.05) reduction in PCR in the Epi state when compared with the basal state. The administration of Epi has a striking effect on EGP profiles: the nadir of the EGP profiles occurs at 21 +/- 7 min in the basal state and at 55 +/- 13 min in the Epi state (P < 0.05). In conclusion, we have shown by use of a two-compartment minimal model of glucose kinetics that elevated plasma Epi concentrations have profound effects at both hepatic and tissue levels. In particular, at the liver site, this hormone deeply affects, in a time-dependent fashion, the inhibitory effect of insulin on glucose release. Our findings may explain how even a normal subject may have the propensity to develop glucose intolerance under the influence of small increments of Epi during physiological stress.     

New stability criterion of neural networks with leakage delays and impulses: a piecewise delay method

This paper analyzes the global asymptotic stability of a class of neural networks with time delay in the leakage term and time-varying delays under impulsive perturbations. Here the time-varying delays are assumed to be piecewise. In this method, the interval of the variation is divided into two subintervals by its central point. By developing a new Lyapunov–Krasovskii functional and checking its variation in between the two subintervals, respectively, and then we present some sufficient conditions to guarantee the global asymptotic stability of the equilibrium point for the considered neural network. The proposed results which do not require the boundedness, differentiability and monotonicity of the activation functions, can be easily verified via the linear matrix inequality (LMI) control toolbox in MATLAB. Finally, a numerical example and its simulation are given to show the conditions obtained are new and less conservative than some existing ones in the literature.     

一类含分布时滞的流行病模型的研究

提出了一类含分布时滞的流行病模型,利用构造李亚普诺夫泛函的方法,得到了无病平衡点和地方病平衡点全局稳定性的结论,揭示了平均时滞对各类平衡点稳定性的影响。     

Glucose tolerance and insulinemia in patients with hepatic cirrhosis and portal hypertension treated by portacaval anastomosis]

Development of diabetes mellitus is a common complication of side to side porta-caval anastomosis (PCA). Five patients with liver cirrhosis and portal hypertension have been studied with intravehous (IVGTT, 0,5 g/Kg B.W.) and oral (OGTT, 1 g/Kg B.W.) glucose tolerance tests before and three weeks after PCA. Fasting plasma glucose was 84 +/- 7 before and 87 +/- 3 mg/dl after PCA. Fasting IRI increased from 17 +/- 3 to 31 +/- 6 microU/ml. The pattern of plasma glucose and IRI response to IVGTT did not change after PCA. Plasma glucose resonse to OGTT after PCA showed only an earlier rise at 60 instead of 90 minutes, whereas IRI resonse (area under the insulin curve) was significantly enhanced (from 12.4 to 19.8 U/l, p < 0.05). These data suggest a role of gut polipeptides in determining hyperinsulinemia and insulin resistence in PCA patients.     

Global Hopf bifurcation analysis of an susceptible-infective-removed epidemic model incorporating media coverage with time delay

An susceptible-infective-removed epidemic model incorporating media coverage with time delay is proposed. The stability of the disease-free equilibrium and endemic equilibrium is studied. And then, the conditions which guarantee the existence of local Hopf bifurcation are given. Furthermore, we show that the local Hopf bifurcation implies the global Hopf bifurcation after the second critical value of delay. The obtained results show that the time delay in media coverage can not affect the stability of the disease-free equilibrium when the basic reproduction number is less than unity. However, the time delay affects the stability of the endemic equilibrium and produces limit cycle oscillations while the basic reproduction number is greater than unity. Finally, some examples for numerical simulations are included to support the theoretical prediction.     

Estimates of in vivo insulin action in humans: comparison of the insulin clamp and the minimal model techniques

The insulin clamp technique, which is often assumed to measure the ability of insulin to stimulate glucose uptake, actually measures both insulin-independent and insulin-dependent glucose uptake. In contrast, the minimal model technique, recently introduced by Bergman, Philips and Cobelli (1981), attempts to directly estimate insulin sensitivity (insulin-dependent glucose uptake = S1) by measurement of plasma glucose and insulin values during a 3 hour intravenous glucose tolerance test (IVGTT). In the present study estimates of insulin action derived from the insulin clamp and the minimal model technique were compared in 20 humans with varying degrees of glucose tolerance. The insulin response during the IVGTT was too low to permit calculation of S1 in 5 subjects - 4 with Type II diabetes and 1 with normal glucose tolerance. Although the correlation coefficient between the two tests in the other 15 patients was statistically significant (r = 0.53, P less than 0.05), this statement is somewhat misleading. Thus, S1 in the 4/7 patients with Type II diabetes in whom it could be measured was zero, and the correlation between estimates of insulin action with the two techniques in the 11 non-diabetic patients was not statistically significant (r = 0.41, P = NS) when these 4 patients were removed from the analysis. In conclusion, these data indicate that there was only a weak correlation between estimates of insulin action assessed with the insulin clamp and the minimal model techniques. One explanation for this observation is that the insulin-independent component of total glucose disposal both varies widely among patients and contributes significantly to glucose uptake as assessed by the insulin clamp technique.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intravenous glucose tolerance, insulin response to glucose, peripheral sensitivity to insulin, and serum lipoproteins in post-myocardial infarct patients with normal fasting blood glucose

Intravenous glucose tolerance (IVGTT), basal insulin and insulin response to glucose infusion (GIT), insulin sensitivity, and lipoprotein patterns were determined in non-obese post-coronary subjects, 3-6 months after myocardial infarction. Twelve had decreased and 31 normal IVGTT. The control group comprised 31 subjects with normal IVGTT, who did not display any signs of coronary disease. The post-coronary patients were not taking any drugs except for furosamide, which was shown not to influence insulin response to GIT or glucose tolerance. Decreased IVGTT in the post-coronary patients could be ascribed to decreased insulin response and insulin resistance. These two derangements are considered as hereditary markers in glucose intolerance and type 2 diabetes. Accordingly, our findings suggest that glucose intolerance in subjects with myocardial infarcts has the same background. The post-coronary patients demonstrated elevated triglycerides (TG) and cholesterol in total serum and in very low density lipoproteins (VLDL), the lipoprotein patterns being almost identical in post-coronary patients with or without decreased IVGTT. No relationship was found in the control and post-coronary groups between IVGTT, basal insulin, stimulated insulin (KI, IP), and insulin sensitivity (KG), on the one hand, and total or VLDL TG or any other lipoprotein particle, on the other. Thus, the derangements in glucose, insulin, and serum triglyceride metabolism were independent abnormalities (risk factors) in these non-obese post-coronary patients.     

Unacylated ghrelin acts as a potent insulin secretagogue in glucose-stimulated conditions

Acylated and unacylated ghrelin (AG and UAG) are gut hormones that exert pleiotropic actions, including regulation of insulin secretion and glucose metabolism. In this study, we investigated whether AG and UAG differentially regulate portal and systemic insulin levels after a glucose load. We studied the effects of the administration of AG (30 nmol/kg), UAG (3 and 30 nmol/kg), the ghrelin receptor antagonist [D-Lys(3)]GHRP-6 (1 micromol/kg), or various combinations of these compounds on portal and systemic levels of glucose and insulin after an intravenous glucose tolerance test (IVGTT, d-glucose 1 g/kg) in anesthetized fasted Wistar rats. UAG administration potently and dose-dependently enhanced the rise of insulin concentration induced by IVGTT in the portal and, to a lesser extent, the systemic circulation. This UAG-induced effect was completely blocked by the coadministration of exogenous AG at equimolar concentrations. Similarly to UAG, [D-Lys(3)]GHRP-6, alone or in combination with AG and UAG, strongly enhanced the portal insulin response to IVGTT, whereas exogenous AG alone did not exert any further effect. Our data demonstrate that, in glucose-stimulated conditions, exogenous UAG acts as a potent insulin secretagogue, whereas endogenous AG exerts a maximal tonic inhibition on glucose-induced insulin release.     

Bolus administration of obestatin does not change glucose and insulin levels neither in the systemic nor in the portal circulation of the rat

Obestatin is a second peptide derived from the preproghrelin polypeptide. It was originally thought to have anorexigenic effects, thereby functioning as an antagonist of ghrelin. However, this has been a subject of debate ever since. Since acylated ghrelin strongly induces insulin resistance, it could be hypothesized that obestatin plays a role in glucose homeostasis as well. In the present study we evaluated the effect of obestatin on glucose and insulin metabolism in the systemic and portal circulation. Obestatin 200 nmol/kg was administered systemically as a single intravenous bolus injection to fasted pentobarbital anesthetized adult male Wistar rats. Up to 50 min after administration, blood samples were taken to measure glucose and insulin concentrations, both in the portal and in the systemic circulation. The effect of obestatin was evaluated in fasted and in glucose-stimulated conditions (IVGTT) and compared to control groups treated with saline or IVGTT, respectively. Intravenous administration of obestatin did not have any effect on glucose and insulin concentrations, neither systemic nor portal, when compared to the control groups. Only the glucose peak 1 min after administration of IVGTT was slightly higher in the obestatin treated rats: 605.8 ± 106.3% vs. 522.2 ± 47.1% in the portal circulation, respectively (NS), and 800.7 ± 78.7% vs. 549.6 ± 37.0% in the systemic circulation, respectively (P < 0.02), but it can be debated whether this has any clinical relevance. In the present study, we demonstrated that intravenously administered obestatin does not influence glucose and insulin concentrations, neither in the portal nor in the systemic circulation.     

Ablation of capsaicin-sensitive afferent nerves affects insulin response during an intravenous glucose tolerance test

We investigated the role of sensory nerves in glucose tolerance in conscious Wistar rats neonatally treated with neurotoxin capsaicin or vehicle. Intravenous glucose tolerance tests (IVGTT, 150, 300 and 450 mg in 30 min) were performed to measure glucose tolerance, and glucose, insulin and glucagon levels were measured. Higher glucose concentration resulted in a greater insulin response in both capsaicin- and vehicle-treated rats. However, glucose-stimulated insulin secretion was attenuated in capsaicin-treated animals, even though glucose levels did not differ. Glucagon levels did not differ between both groups. These results show that capsaicin-sensitive nerves are involved in glucose-stimulated insulin secretion, but are not directly involved in the regulation of blood glucose levels. Moreover, they suggest that capsaicin-sensitive nerves could be involved in the regulation of insulin sensitivity. We hypothesize that sensory afferents could play a role in the aetiology of pathologies where glucohomeostatic mechanisms are disturbed, as is in type 2 diabetes mellitus.