Effects of ketamine sedation on glucose clearance, insulin secretion and counterregulatory hormone production in baboons (<i>Papio hamadryas</i>)

Lehmann, Roger; Wagner, Joseph; Fernández, Luis A.; Bourgoignie, Jacques J.; Ricordi, Camillo; Alejandro, Rodolfo; Kenyon, Norma S.

doi:10.1111/j.1600-0684.1997.tb00060.x

Cited by 19 publications

(17 citation statements)

References 46 publications

(8 reference statements)

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“…Ketamine in doses greater than those used in the present study has been shown to decrease circulating GH concentrations in baboons (Lehmann et al 1997). In another study no significant difference was observed in plasma GH concentrations in rhesus monkeys sedated with phencyclidine compared with those in conscious animals (Wheeler & Styne 1988).…”

Section: Discussioncontrasting

confidence: 49%

Testosterone modulates growth hormone secretion at the hypothalamic but not at the hypophyseal level in the adult male rhesus monkey

Rizvi

Weinbauer²,

Arslan³

et al. 2000

Journal of Endocrinology

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We investigated a possible modulation of growth hormone (GH) secretion by testosterone by measuring the growth hormone releasing hormone (GHRH)-stimulated and N-methyl-,-aspartic acid (NMA)-induced GH secretion in adult rhesus monkeys. Intact, orchidectomized and testosterone-substituted (testosterone enanthate 125 mg/ week, i.m. for 5 weeks) orchidectomized monkeys (n=5) were used in the study. GHRH (25 µg/kg body weight) or NMA (15 mg/kg body weight) was infused through a Teflon cannula implanted in the saphenous vein. Sequential blood samples were collected 30-60 min before and 60 min after the injection of the neurohormone or the drug at 10-20-min intervals. All bleedings were carried out under ketamine hydrochloride anaesthesia (initial dose 5 mg/kg body weight i.m., followed by 2·5 mg/kg at 30-min intervals). The plasma concentrations of GH, testosterone and oestradiol (E 2 ) were determined by using specific assay systems. Administration of GHRH elicited a significant increase in GH secretion in all three groups of animals. There was no significant difference in the responsiveness of pituitary somatotrophs to exogenous GHRH challenges between intact and orchidectomized monkeys and testosterone replacement in orchidectomized animals did not significantly alter the GHRH-induced GH response. The responsiveness of hypothalamic GHRH neurones apparently did undergo a qualitative change after orchidectomy, as GH response to NMA was less in orchidectomized animals than in intact monkeys. The responsiveness of GHRH neurones to exogenous NMA was restored and even potentiated when orchidectomized monkeys were treated with testosterone. Taken together, these findings suggest that testosterone does not affect the sensitivity of the pituitary somatotrophs to GHRH but stimulates the secretion of GH by modulation of the NMDA drive to GHRH neurones.

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Section: Discussioncontrasting

confidence: 49%

Testosterone modulates growth hormone secretion at the hypothalamic but not at the hypophyseal level in the adult male rhesus monkey

Rizvi

Weinbauer²,

Arslan³

et al. 2000

Journal of Endocrinology

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“…Ketamine-induced sedation has been shown to modestly suppress plasma glucose and insulin concentrations in baboons [15] possibly accounting for the relatively low fasting plasma glucose concentrations observed in this study. However, a stable and consistent plane of anesthesia is achievable by the protocol used [16] and any differences between groups treated with different agents should be attributable to the compounds per se.…”

Section: Discussionmentioning

confidence: 62%

Pharmacologic restoration of the early insulin response in pre-diabetic monkeys controls mealtime glucose excursions without peripheral hyperinsulinaemia

Gutiérrez

et al. 2003

Diabetologia

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Aims/hypothesis. This study sought first to compare the pharmacodynamics and pharmocokinetics of two rapid-onset, rapidly-reversible insulinotropic agents, nateglinide and repaglinide, in pre-diabetic Cynomolgus monkeys and second to use these agents to assess the metabolic effects of early insulin secretion on prandial glucose control. Methods. First, equipotent doses of nateglinide (20 mg/kg) and repaglinide (0.1 mg/kg) or vehicle were given intragastrically to overnight-fasted ketamine-anesthetized pre-diabetic Cynomolgus monkeys and samples were obtained for measurement of plasma glucose, insulin, glucagon, NEFA and drug concentrations. Second, nateglinide, repaglinide or vehicle were administered 10 min before a glucosesupplemented liquid meal and prandial glucose and insulin profiles were compared. Results. Although oral administration of nateglinide and repaglinide elicited similar maximum increments of plasma insulin (+403 and +448 pmol/l, respectively), the effects of nateglinide were more rapidly manifest and less prolonged. With nateglinide, insulin increased within 10 min and returned to baseline within 50 min. After repaglinide, the first increase occurred at 30 min and insulin concentrations remained increased for 3.5 h post-dose. When given 10 min before a meal, nateglinide increased early, but not total insulin release (AUC 0-210 =108 vs 150 nmol/l min for nateglinide and vehicle, respectively) and reduced prandial glucose excursions by 78%. Repaglinide increased total insulin release (AUC 0-210 =298 nmol/l min) and reduced glucose excursions by 53%. Conclusion/interpretation. Nateglinide is more rapidacting and rapidly-reversible than is repaglinide. By restoring a more physiologic insulin profile, nateglinide is more effective than repaglinide in controlling prandial glucose excursions with less hyperinsulinaemia. It has been shown convincingly that in Type 2 (noninsulin-dependent) diabetes mellitus [1,2] and even in precursors thereof [3] the kinetics of insulin secretion are disrupted despite the existence of absolute (if not relative) hyperinsulinaemia. The disrupted insulin secretory kinetics can be confirmed by either the absence of the acute insulin response to i.v. glucose [4] or a sluggish insulin response to oral glucose [5] or a meal [6]. The impaired early insulin response leads to a marked impairment of the suppression of endogenous glucose production normally seen after glucose administration or a meal [5,6] and to a lesser extent, a later decrease of peripheral glucose utilization [6].

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“…Additional ketamine was administered as needed. Because it has been demonstrated that ketamine reduces first-phase insulin release, we kept the ketamine dose as low as possible for the purposes of metabolic testing (39). Animals also were physically restrained with a restraining board during performance of intravenous glucose tolerance tests (IVGTTs).…”

Section: Methodsmentioning

confidence: 99%

“…It has previously been demonstrated that first-phase insulin release (FPIR) in response to intravenous glucose tolerance testing provides an accurate reflection of ␤ cell mass (46). After an overnight fast, blood samples of 1.5 ml each were collected at 10, 5, and 0 minutes before the infusion of glucose, followed by intravenous administration (cephalic vein) of 0.5 g of glucose per kg of recipient body weight, as described (39). Subsequent samples were collected from the contralateral femoral artery at 1, 3, 5, 7, 10, 15, 20, 25, and 30 minutes after the injection of glucose.…”

Section: Methodsmentioning

confidence: 99%

Long-term survival and function of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CD154

Kenyon

Chatzipetrou

Masetti

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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396

250

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Reported effects of anti-CD154 treatment on autoimmunity, alloreactivity, and inf lammatory events mediated by macrophages and endothelial cells indicated that it might be an ideal agent for the prevention of intrahepatic islet allograft failure. This hypothesis was tested in MHCmismatched rhesus monkeys. Transplantation of an adequate number of viable islets resulted in engraftment and insulin independence in six of six recipients treated with anti-CD154 (hu5c8) induction plus monthly maintenance therapy (postoperative day >125, >246, >266, >405, >419, >476). Anti-CD154 (hu5c8) displayed no inhibitory effect on islet cell function. For monkeys followed for >100 days, continued improvement in graft function, as determined by first phase insulin release in response to intravenous glucose, was observed after the first 100 days post-transplant. No evidence of toxicity or infectious complications has been observed. All recipients treated with anti-CD154 became specifically nonresponsive to donor cells in mixed lymphocyte reactions. Furthermore, three monkeys are now off therapy (>113, >67, and >54 days off anti-CD154), with continued insulin independence and donor-specific mixed lymphocyte reaction hyporeactivity. In striking contrast to all previously tested strategies, transplantation of an adequate number of functional islets under the cover of anti-CD154 (hu5c8) monotherapy consistently allows for allogeneic islet engraftment and long-term insulin independence in this highly relevant preclinical model.Islet cell transplantation for patients with type 1 diabetes can result in the reversal of hyperglycemia and normalization of metabolic control (1-7). Broad-based application of curative islet cell transplantation has been limited, however, by the inability of current, generalized immunosuppressive reagents to reliably support long-term islet graft survival and function. The CD40-CD154 costimulation pathway has proven to be a critical interaction in the generation of a T-dependent immune response (8-10), and blockade of this pathway has prevented allograft rejection (11-16), graft versus host disease (17-19), and autoimmunity (20-29) in rodent models. Humanized anti-CD154 (30) (hu5c8, Biogen) has been shown to prevent renal allograft rejection in a rigorous non-human primate model (31). Additionally, blockade of the CD40-CD154 costimulation pathway can prevent production of proinflammatory mediators by activated macrophages (32-34) and endothelial cells (35)(36). Blockade of this pathway, therefore, has the potential to prevent allograft rejection, recurrent autoimmunity, and the nonspecific inflammatory events that occur on transplantation of islets into the liver, without the adverse effects of conventional, generalized immunosuppressive drugs on islet function (37). This study was undertaken to determine whether anti-CD154 (hu5c8) monotherapy would prevent the rejection of allogeneic islets in a preclinical, non-human primate model of pancreatectomy-induced diabetes.

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Effects of ketamine sedation on glucose clearance, insulin secretion and counterregulatory hormone production in baboons (Papio hamadryas)

Cited by 19 publications

References 46 publications

Testosterone modulates growth hormone secretion at the hypothalamic but not at the hypophyseal level in the adult male rhesus monkey

Testosterone modulates growth hormone secretion at the hypothalamic but not at the hypophyseal level in the adult male rhesus monkey

Pharmacologic restoration of the early insulin response in pre-diabetic monkeys controls mealtime glucose excursions without peripheral hyperinsulinaemia

Long-term survival and function of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CD154

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