Mathematical Model of Glucagon Kinetics for the Assessment of Insulin-Mediated Glucagon Inhibition During an Oral Glucose Tolerance Test

none6siGlucagon is secreted from the pancreatic alpha cells and plays an important role in the maintenance of glucose homeostasis, by interacting with insulin. The plasma glucose levels determine whether glucagon secretion or insulin secretion is activated or inhibited. Despite its relevance, some aspects of glucagon secretion and kinetics remain unclear. To gain insight into this, we aimed to develop a mathematical model of the glucagon kinetics during an oral glucose tolerance test, which is sufficiently simple to be used in the clinical practice. The proposed model included two first-order differential equations -one describing glucagon and the other describing C-peptide in a compartment remote from plasma - and yielded a parameter of possible clinical relevance (i.e., SGLUCA(t), glucagon-inhibition sensitivity to glucose-induced insulin secretion). Model was validated on mean glucagon data derived from the scientific literature, yielding values for SGLUCA(t) ranging from -15.03 to 2.75 (ng of glucagon·nmol of C-peptide-1). A further validation on a total of 100 virtual subjects provided reliable results (mean residuals between -1.5 and 1.5 ng·L-1) and a negative significant linear correlation (r = -0.74, p < 0.0001, 95% CI: -0.82 - -0.64) between SGLUCA(t) and the ratio between the areas under the curve of suprabasal remote C-peptide and glucagon. Model reliability was also proven by the ability to capture different patterns in glucagon kinetics. In conclusion, the proposed model reliably reproduces glucagon kinetics and is characterized by sufficient simplicity to be possibly used in the clinical practice, for the estimation in the single individual of some glucagon-related parameters.openMorettini, Micaela; Burattini, Laura; Göbl, Christian; Pacini, Giovanni; Ahrén, Bo; Tura, AndreaMorettini, Micaela; Burattini, Laura; Göbl, Christian; Pacini, Giovanni; Ahrén, Bo; Tura, Andre

Mathematical model of insulin kinetics accounting for the amino acids effect during a mixed meal tolerance test

Amino acids (AAs) are well known to be involved in the regulation of glucose metabolism and, in particular, of insulin secretion. However, the effects of different AAs on insulin release and kinetics have not been completely elucidated. The aim of this study was to propose a mathematical model that includes the effect of AAs on insulin kinetics during a mixed meal tolerance test. To this aim, five different models were proposed and compared. Validation was performed using average data, derived from the scientific literature, regarding subjects with normal glucose tolerance (CNT) and with type 2 diabetes (T2D). From the average data of the CNT and T2D people, data for two virtual populations (100 for each group) were generated for further model validation. Among the five proposed models, a simple model including one first-order differential equation showed the best results in terms of model performance (best compromise between model structure parsimony, estimated parameters plausibility, and data fit accuracy). With regard to the contribution of AAs to insulin appearance/disappearance (kAA model parameter), model analysis of the average data from the literature yielded 0.0247 (confidence interval, CI: 0.0168 - 0.0325) and -0.0048 (CI: -0.0281 - 0.0185) μU·ml-1/(μmol·l-1·min), for CNT and T2D, respectively. This suggests a positive effect of AAs on insulin secretion in CNT, and negligible effect in T2D. In conclusion, a simple model, including single first-order differential equation, may help to describe the possible AAs effects on insulin kinetics during a physiological metabolic test, and provide parameters that can be assessed in the single individuals

Next generation sequencing study on RNA viruses of Vespa velutina and Apis mellifera sharing the same foraging area

The predator Asian hornet (Vespa velutina) represents one of the major threats to honeybee survival. Viral spillover from bee to wasp has been supposed in several studies, and this work aims to identify and study the virome of both insect species living simultaneously in the same foraging area. Transcriptomic analysis was performed on V. velutina and Apis mellifera samples, and replicative form of detected viruses was carried out by strand‐specific RT‐PCR. Overall, 6 and 9 different viral types were reported in V. velutina and A. mellifera, respectively, and five of these viruses were recorded in both hosts. Varroa destructor virus‐1 and Cripavirus NB‐1/2011/HUN (now classified as Triato‐like virus) were the most represented viruses detected in both hosts, also in replicative form. In this investigation, Triato‐like virus, as well as Aphis gossypii virus and Nora virus, was detected for the first time in honeybees. Concerning V. velutina, we report for the first time the recently detected honeybee La Jolla virus. A general high homology rate between genomes of shared viruses between V. velutina and A. mellifera suggests the efficient transmission of the virus from bee to wasp. In conclusion, our findings highlight the presence of several known and newly reported RNA viruses infecting A. mellifera and V. velutina. This confirms the environment role as an important source of infection and indicates the possibility of spillover from prey to predator

Astragalus membranaceus and oxaliplatin-induced neuropathy: pain relief and prevention of nervous tissue modifications

Neurotoxicity is the limiting side effect of the anticancer agent oxaliplatin. A tangled panel of symptoms, sensory loss, paresthesia, dysesthesia, pain may be disabling for patients adversely affecting quality of life. Pharmacological treatments demonstrating a therapeutic effect on oxaliplatin’s cumulative neurotoxicity are unsatisfactory and limited to symptomatic effects. Astragalus membranaceus is an adaptogenic herb from the traditional Chinese medicine. Aimed to study the antineuropathic profile of this plant, a hydroalcoholic extract from selected roots of A. membranaceus was obtained and characterized. A. membranaceus extract was tested in a rat model of painful oxaliplatin-induced neuropathy (2.4 mgkg-1 intraperitoneally, daily for 21 days). The extract was administered per os (300 mgkg-1) once a day, starting from the first day of oxaliplatin injection until the 20th. On day 21 A. membranaceus extract treatment was able to significantly reduce oxaliplatin-dependent pain, when evaluated as an increase on suprathreshold stimulation (hyperalgesia-related measure) or as a decrease in pain threshold (allodyniarelated measure). The extract strongly prevented the serious nephro- and hepato-toxicity induced by repeated treatment with the anticancer drug. In the nervous system the hydroalcoholic extract reduced the morphometric alterations induced by oxaliplatin in the dorsal root ganglia, and significantly prevented the changes in the activating transcription factor 3 and in the phosphorylated heavy chain of neurofilament expression levels both in nerves and ganglia. In the dorsal horn of the spinal cord and in pain related cerebral areas A. membranaceus extract prevented the oxaliplatininduced increase of glial density. The hydroalcoholic extract of Astragalus membranaceus relieves pain and promotes the rescue mechanisms that protect nervous tissue from the damages triggering chronic pain. A safe profile strongly suggests the usefulness of this natural product in oxaliplatin-induced neuropathy

Involvement of Alpha7 nAC hR downregulation in rat oxaliplatin-induced neuropathy

Oxaliplatin, unlike other platinum derivatives, does not result in significant renal impairment or ototoxicity, and it has only mild hematological and gastrointestinal toxicity. On the other hand the limiting side effect is its neurotoxicity that acts as bases for a neuropathic syndrome. A tangled panel of symptoms may be disabling for these patients, adversely affecting activities of daily living and thereby quality of life. In a rat model of painful oxaliplatin-induced neuropathy, we are describing a pattern of molecular and morphological alterations of both the peripheral and the central nervous system. Among them an important activation of the glial component has been evidenced. Alpha7 nAChR is widely expressed throughout the CNS. It has been described in neurons, microglia and astrocytes, where it seems to play a modulatory role. Moreover, alpha7 nAChR stimulation induces antihyperalgesic and neuroprotective effects in trauma-induced neuropathy. Aimed to study the pathophysiological mechanism of the chemotherapy-dependent neuropathy, the role of the alpha7 nAChR was investigated in the rat model of oxaliplatin- induced neuropathy (2.4 mgkg-1 intraperitoneally, daily injected for 21 days). At day 21th, when neuropathic pain is well established, alpha7 nAChR protein level expression was dramatically decreased both in the peripheral and in the central nervous system. The repeated treatment with the alpha7 nAChR agonist PNU-282987 (30 mgkg-1 p. os, daily administered for 21 days, starting from the first oxaliplatin injection) was able to prevent mechanical hyperalgesia (evaluated by Paw pressure test). Moreover, mechanical (evaluated by Von Frey test) and thermal allodynia (evaluated by Cold Plate test) were significantly reduced. Repeated treatment with PNU- 282987 was also able to improve motor coordination (evaluated by Rota-rod test). Western blot analysis revealed that the repeated treatment with the agonist prevented the decrease of alpha7 protein level in a significative manner. Further ex vivo analysis of the nervous system showed a PNU-282987 neuroprotective effect: in morphological terms, in the dorsal root ganglia, and in the peripheral nerve and in the spinal cord as indicated by molecular parameters. These results strongly suggest the pivotal role of alpha7 nAChR in the neuroprotection during neuropathy

Astragali radix: could it be an adjuvant for oxaliplatin-induced neuropathy?

Neurotoxicity is a major side effect of platinum derivatives both during and after treatment. In the absence of effective pharmacological compounds, the opportunity to identify safe adjuvant treatments among medicinal plants seems appropriate. Astragali radix is an adaptogenic herbal product recently analyzed in platinum-treated cancer patients. With the aim of evaluating the anti-neuropathic profile of Astragali radix, a previously characterized aqueous (Aqu) and two hydroalcoholic (20%HA and 50%HA) extracts were tested in a rat model of oxaliplatin-induced neuropathy. Repeated administrations significantly reduced oxaliplatin-dependent hypersensitivity with 50%HA, the most effective, fully preventing mechanical and thermal hypersensitivity. Ex vivo, 50%HA reduced morphometric and molecular alterations induced by oxaliplatin in peripheral nerve and dorsal-root-ganglia. In the spinal cord and in brain areas, 50%HA significantly decreased activation of microglia and astrocytes. Furthermore, 50%HA prevented the nephro- and hepato-toxicity induced by the anticancer drug. The protective effect of 50%HA did not alter oxaliplatin-induced apoptosis in colon tumors of Pirc rats, an Apc-driven model of colon carcinogenesis. The hydroalcoholic extract (50%HA) of Astragali radix relieves pain and promotes the rescue mechanisms that protect nervous tissue from the damages triggering chronic pain. A safe profile strongly suggests the usefulness of this natural product in oxaliplatin-induced neuropathy