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1.
2.
《Bioorganic & medicinal chemistry letters》2014,24(4):1031-1036
We report the discovery of the glucose-dependent insulin secretogogue activity of a novel class of polycyclic guanidines through phenotypic screening as part of the Lilly Open Innovation Drug Discovery platform. Three compounds from the University of California, Irvine, 1–3, having the 3-arylhexahydropyrrolo[1,2-c]pyrimidin-1-amine scaffold acted as insulin secretagogues under high, but not low, glucose conditions. Exploration of the structure–activity relationship around the scaffold demonstrated the key role of the guanidine moiety, as well as the importance of two lipophilic regions, and led to the identification of 9h, which stimulated insulin secretion in isolated rat pancreatic islets in a glucose-dependent manner. 相似文献
3.
Short-term disappearance of muscarinic cell surface receptors in carbachol-induced desensitization 总被引:3,自引:0,他引:3
N6-Phenylisopropyladenosine was employed in the absence of endogenous adenosine to explore the influence exerted by the R-site over the antagonistic interaction of insulin and catecholamines on several parameters of fat cell metabolism. When no hormones were present, N6-phenylisopropyladenosine had little or no effect; however, the nucleoside potentiated insulin inhibition of catecholamine-stimulated events, such as lipolysis, and, conversely, diminished or blocked catecholamine inhibition of insulin-stimulated processes, such as 2-deoxyglucose uptake, glucose oxidation and esterification, even under conditions where N6-phenylisopropyladenosine, alone, was ineffective in reversing catecholamine actions. 相似文献
4.
W.J. Malaisse F. Malaisse-Lagae A. Sener 《Biochimica et Biophysica Acta (BBA)/General Subjects》1984,797(2):194-202
1. Because L-asparagine augments insulin release evoked by L-leucine, the metabolism of these two amino acids was investigated in rat pancreatic islets. 2. L-Leucine inhibited the uptake and deamidation of L-asparagine, but failed to exert any obvious primary effect upon the further catabolism of aspartate derived from exogenous asparagine. 3. L-Asparagine augmented the oxidation of L-leucine, and effect possibly attributable to activaion of 2-ketoisocaproate dehydrogenase. 4. The association of L-asparagine and L-leucine exerted a sparing action on the utilization of endogenous amino acids, so that the integrated rate of nutrients oxidation was virtually identical in the sole presence of L-leucine and simultaneous presence of L-asparagine and L-leucine, respectively. 5. It is proposed that the enhancing action of L-asparagine upon insulin release evoked by L-leucine is attributable to an increased generation rate of cytosolic NADPH rather than any increase in nutrients oxidation. 相似文献
5.
《Saudi Journal of Biological Sciences》2020,27(11):2968-2971
BackgroundAmomum villosum Lour., (Zingiberaceae) an herbaceous plant in the ginger family, has been used to treat various diseases. In a single-blind, randomized, crossover study, we assessed the postprandial blood insulin and blood glucose responses in healthy subjects (n = 40) after the Amomum villosum water extract (AVE) (5 g/person) or a placebo (5 g/person) consumption.MethodsDuring each treatment course, the healthy subject consumed a regular late afternoon meal, followed by fasting for 12 h, and arrived at the clinical study center the next morning. Blood insulin and blood glucose levels were assessed at 0, 30, 60, 90, and 120 min after AVE consumption. Between each treatment, the subjects accomplished one week of a washout period.ResultsThe AVE intake demonstrated a significant (67.26%) decline in postprandial blood glucose AUC0–120 min (incremental area under the curve from 0 to 120 min) versus the placebo (P = 0.011). Furthermore, AVE reduced postprandial blood insulin AUC0–120 min by 59.95% compared to the placebo group (P < 0.003), supporting the blood glucose results.ConclusionThis study revealed that AVE consumption significantly reduced postprandial insulin and glucose levels in healthy individuals, due in part to inhibition of α-glucosidase, and glucose transport. 相似文献
6.
Nitric oxide synthase (NOS) may be uncoupled to produce superoxide rather than nitric oxide (NO) under pathological conditions such as diabetes mellitus and insulin resistance, leading to cardiac contractile anomalies. Nonetheless, the role of NOS uncoupling in insulin resistance-induced cardiac dysfunction remains elusive. Given that folic acid may produce beneficial effects for cardiac insufficiency partially through its NOS recoupling capacity, this study was designed to evaluate the effect of folic acid on insulin resistance-induced cardiac contractile dysfunction in a sucrose-induced insulin resistance model. Mice were fed a sucrose or starch diet for 8 weeks before administration of folic acid in drinking water for an additional 4 weeks. Cardiomyocyte contractile and Ca2+ transient properties were evaluated and myocardial function was assessed using echocardiography. Our results revealed whole body insulin resistance after sucrose feeding associated with diminished NO production, elevated peroxynitrite (ONOO−) levels, and impaired echocardiographic and cardiomyocyte function along with a leaky ryanodine receptor (RYR) and intracellular Ca2+ handling derangement. Western blot analysis showed that insulin resistance significantly promoted Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation, which might be responsible for the leaky RYR and cardiac mechanical dysfunction. NOS recoupling using folic acid reversed insulin resistance-induced changes in NO and ONOO−, CaMKII phosphorylation, and cardiac mechanical abnormalities. Taken together, these data demonstrated that treatment with folic acid may reverse cardiac contractile and intracellular Ca2+ anomalies through ablation of CaMKII phosphorylation and RYR Ca2+ leak. 相似文献
7.
Hans-Jürgen Hahn Erik Gylfe Bo Hellman 《Biochimica et Biophysica Acta (BBA)/General Subjects》1980,630(3):425-432
The effect of cyclic AMP on calcium movements in the pancreatic β-cell was evaluated using an experimental approach based on in situ labelling of intracellular organelles of ob/ob-mouse islets with 45Ca. Whereas the glucose-stimulated 45Ca incorporation by mitochondria and secretory granules was increased under a condition known to reduce cyclic AMP (starvation), raised levels of this nucleotide (addition of 3-isobutyl-1-methylxanthine or N6,O2′-dibutyryl adenosine 3′,5′-cyclic monophosphate) reduced the mitochondrial accumulation of 45Ca. Conditions with increased cyclic AMP were associated with a stimulated efflux of 45Ca from the secretory granules but not from the mitochondria. The microsomal fraction differed from both the mitochondrial and secretory granule fractions by accumulating more 45Ca after the addition of 3-isobutyl-1-methylxanthine. The results suggest that cyclic AMP potentiates glucose-stimulated insulin release by increasing cytoplasmic Ca2+ at the expense of the calcium taken up by the organelles of the pancreatic β-cells. 相似文献
8.
The early intracellular signaling pathway for the insulin/insulin-like growth factor receptor family in the mammalian central nervous system 总被引:8,自引:0,他引:8
Franco Folli Silvana Ghidella Luca Bonfanti C. Ronald Kahn Adalberto Merighi 《Molecular neurobiology》1996,13(2):155-183
Several studies support the idea that the polypeptides belonging to the family of insulin and insulin-like growth factors
(IGFs) play an important role in brain development and continue to be produced in discrete areas of the adult brain. In numerous
neuronal populations within the olfactory bulb, the cerebral and cerebellar cortex, the hippocampus, some diencephalic and
brainstem nuclei, the spinal cord and the retina, specific insulin and IGF receptors, as well as crucial components of the
intracellular receptor signaling pathway have been demonstrated. Thus, mature neurons are endowed with the cellular machinery
to respond to insulin and IGF stimulation. Studies in vitro and in vivo, using normal and transgenic animals, have led to
the hypothesis that, in the adult brain, IGF-I not only acts as a trophic factor, but also as a neuromodulator of some higher
brain functions, such as long-term potentiation and depression. Furthermore, a trophic effect on certain neuronal populations
becomes clearly evident in the ischemic brain or neurodegenerative disorders. Thus, the analysis of the early intracellular
signaling pathway for the insulin/IGF receptor family in the brain is providing us with new intriguing findings on the way
the mammalian brain is sculpted and operates. 相似文献
9.
This article is part of a Special Issue Energy Balance. 相似文献
10.
Bernard Thorens 《Molecular membrane biology》2013,30(4):265-273
Detection of variations in blood glucose concentrations by pancreatic g -cells and a subsequent appropriate secretion of insulin are key events in the control of glucose homeostasis. Because a decreased capability to sense glycemic changes is a hallmark of type 2 diabetes, the glucose signalling pathway leading to insulin secretion in pancreatic g -cells has been extensively studied. This signalling mechanism depends on glucose metabolism and requires the presence of specific molecules such as GLUT2, glucokinase and the K ATP channel subunits Kir6.2 and SUR1. Other cells are also able to sense variations in glycemia or in local glucose concentrations and to modulate different physiological functions participating in the general control of glucose and energy homeostasis. These include cells forming the hepatoportal vein glucose sensor, which controls glucose storage in the liver, counterregulation, food intake and glucose utilization by peripheral tissues and neurons in the hypothalamus and brainstem whose firing rates are modulated by local variations in glucose concentrations or, when not protected by a blood-brain barrier, directly by changes in blood glucose levels. These glucose-sensing neurons are involved in the control of insulin and glucagon secretion, food intake and energy expenditure. Here, recent physiological studies performed with GLUT2 -/- mice will be described, which indicate that this transporter is ess ential for glucose sensing by pancreatic g -cells, by the hepatoportal sensor and by sensors, probably located centrally, which control activity of the autonomic nervous system and stimulate glucagon secretion. These studies may pave the way to a fine dissection of the molecular and cellular components of extra-pancreatic glucose sensors involved in the control of glucose and energy homeostasis. 相似文献