Glucagon challenge in the rat: A robust method for the in vivo assessment of Glycogen phosphorlyase inhibitor efficacy

Loxham, Susan J. G.; Teague, Joanne; Poucher, Simon M.; Schoolmeester, J. de; Turnbull, Andrew V.; Carey, Frank

doi:10.1016/j.vascn.2006.03.005

Cited by 21 publications

(19 citation statements)

References 15 publications

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“…Our finding of an earlier rise in blood glucose after intraperitoneally injected glucagon, compared with subcutaneous injection, is difficult to compare with previous studies as blood glucose was measured at different time points and intervals. In previous studies, blood glucose was only measured 20 24 and 30 25 min after glucagon injection. Moreover, the study by Zlotnik et al 25 provided only data of intraperitoneal glucagon injection.…”

Section: Discussionmentioning

confidence: 99%

Intraperitoneal, subcutaneous and intravenous glucagon delivery and subsequent glucose response in rats: a randomized controlled crossover trial

Dirnena-Fusini

Åm²,

Fougner

et al. 2018

BMJ Open Diab Res Care

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ObjectiveHypoglycemia is a frequent and potentially dangerous event among patients with diabetes mellitus type 1. Subcutaneous glucagon is an emergency treatment to counteract severe hypoglycemia. The effect of intraperitoneal glucagon delivery is sparsely studied. We performed a direct comparison of the blood glucose response following intraperitoneally, subcutaneously and intravenously administered glucagon.Research design and methodsThis is a prospective, randomized, controlled, open-label, crossover trial in 20 octreotide-treated rats. Three interventions, 1 week apart, in a randomized order, were done in each rat. All 20 rats were given intraperitoneal and subcutaneous glucagon injections, from which 5 rats were given intravenous glucagon injections and 15 rats received placebo (intraperitoneal isotonic saline) injection. The dose of glucagon was 5 µg/kg body weight for all routes of administration. Blood glucose levels were measured before and until 60 min after the glucagon/placebo injections.ResultsCompared with placebo-treated rats, a significant increase in blood glucose was observed 4 min after intraperitoneal glucagon administration (p=0.009), whereas after subcutaneous and intravenous glucagon administration significant increases were seen after 8 min (p=0.002 and p<0.001, respectively). In intraperitoneally treated compared with subcutaneously treated rats, the increase in blood glucose was higher after 4 min (p=0.019) and lower after 40 min (p=0.005) and 50 min (p=0.011). The maximum glucose response occurred earlier after intraperitoneal compared with subcutaneous glucagon injection (25 min vs 35 min; p=0.003).ConclusionsGlucagon administered intraperitoneally gives a faster glucose response compared with subcutaneously administered glucagon in rats. If repeatable in humans, the more rapid glucose response may be of importance in a dual-hormone artificial pancreas using the intraperitoneal route for administration of insulin and glucagon.

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Section: Discussionmentioning

confidence: 99%

Intraperitoneal, subcutaneous and intravenous glucagon delivery and subsequent glucose response in rats: a randomized controlled crossover trial

Dirnena-Fusini

Åm²,

Fougner

et al. 2018

BMJ Open Diab Res Care

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“…At the end of the feeding trial (experimental day 35), the rats were fasted overnight and then weighed after which fasting blood glucose was determined from blood drawn following a tail vein prick (Loxham et al., ) using a calibrated Accu‐Achek Active glucometer (Roche, Mannheim, Germany) as per the manufacturer's instructions. Immediately after the determination of fasting blood glucose concentration, each rat was euthanased by the intraperitoneal administration of pentobarbital (Canteur Laboratories, Johannesburg, South Africa) at 150 mg/kg.…”

Section: Methodsmentioning

confidence: 99%

Dietary effects of Moringa oleifera leaf powder on growth, gastrointestinal morphometry and blood and liver metabolites in Sprague Dawley rats

Zvinorova

Lekhanya

Erlwanger

et al. 2014

Animal Physiology Nutrition

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We investigated the effects of Moringa oleifera leaf powder (MOLP) as a dietary supplement on growth performance, gastrointestinal (GIT) morphometry and liver function using weanling Sprague Dawley rats to model humans under ad libitum and restricted feeding. An MOLP-based diet was generated by supplementing normal rat feed with the leaf powder at 20%. Four dietary regimens included normal rat feed fed at 20% of body mass (NRF: ad libitum), NRF fed at 14% of body mass (NRFR, restricted), Moringa-supplemented feeds fed at 20% and 14% of body mass (MOF: ad libitum and MOFR: restrictedly) respectively. Thirty-two pups were randomly assigned to the diets and fed for 5 weeks, after which they were fasted, euthanased and GIT viscera masses, lengths and histology were assessed. Blood was collected for metabolite and markers of liver function assays. Tibiae and femora lengths were used to determine linear growth. Rats fed the restricted diets had lower weekly body mass gains (p = 0.0001) than those on ad libitum feeding; however, they showed compensatory growth by 5 weeks. Terminally, the rats fed MOFR had shorter (p < 0.05) femora and tibiae than their counterparts on the other diets. Except on the caeca, diet had no effect on the absolute masses and lengths of GIT viscera. Relative to tibia length, rats on the MOF had significantly heavier stomachs and caeca and longer small and large intestines than their counterparts on NRF, but this was not supported histologically. Level of feeding and supplementation did not affect blood metabolite concentration, liver glycogen and lipid storage nor the plasma activities AST and ALP in the rats. Supplementing diets with MOLP under restricted access to feed (low calorific supply) might compromise linear growth.

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“…In vivo potency of GPi688 was measured in both Wistar and Zucker ( fa/fa ) male rats (AstraZeneca Biological Services) using a glucagon challenge to induce hyperglycaemia (Loxham et al , 2007). The efficacy of GPi688 was also assessed against an oral glucose tolerance test in obese Zucker rats.…”

Section: Methodsmentioning

confidence: 99%

An assessment of the in vivo efficacy of the glycogen phosphorylase inhibitor GPi688 in rat models of hyperglycaemia

Poucher

Freeman

Loxham

et al. 2007

British J Pharmacology

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Background and purpose: Studies in cultured hepatocytes demonstrate glycogen synthase (GS) activation with glycogen phosphorylase (GP) inhibitors. The current study investigated whether these phenomena occurred in vivo using a novel GP inhibitor. Experimental approach: An allosteric GP inhibitor, GPi688, was evaluated against both glucagon-mediated hyperglycaemia and oral glucose challenge-mediated hyperglycaemia to determine the relative effects against GP and GS in vivo. Key results: In rat primary hepatocytes, GPi688 inhibited glucagons-mediated glucose output in a concentration dependent manner. Additionally GP activity was reduced and GS activity increased seven-fold. GPi688 inhibited glucagon-mediated hyperglycaemia in both Wistar (65%) & obese Zucker (100%) rats and demonstrated a long duration of action in the Zucker rat. The in vivo efficacy in the glucagon challenge model could be predicted by the equation; % glucagon inhibition ¼ 56.9 þ 34.3[log ([free plasma]/rat IC 50 )], r ¼ 0.921). GPi688 also reduced the blood glucose of obese Zucker rats after a 7 h fast by 23%. In an oral glucose tolerance test in Zucker rats, however, GPi688 was less efficacious (7% reduction) than a glycogen synthase kinase-3 (GSK-3) inhibitor (22% reduction), despite also observing activation (by 45%) of GS in vivo. Conclusions and implications: Although GP inhibition can inhibit hyperglycaemia mediated by increased glucose production, the degree of GS activation induced by allosteric GP inhibitors in vivo, although discernible, is insufficient to increase glucose disposal. The data suggests that GP inhibitors might be more effective clinically against fasting rather than prandial hyperglycaemic control.

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Glucagon challenge in the rat: A robust method for the in vivo assessment of Glycogen phosphorlyase inhibitor efficacy

Cited by 21 publications

References 15 publications

Intraperitoneal, subcutaneous and intravenous glucagon delivery and subsequent glucose response in rats: a randomized controlled crossover trial

Intraperitoneal, subcutaneous and intravenous glucagon delivery and subsequent glucose response in rats: a randomized controlled crossover trial

Dietary effects of Moringa oleifera leaf powder on growth, gastrointestinal morphometry and blood and liver metabolites in Sprague Dawley rats

An assessment of the in vivo efficacy of the glycogen phosphorylase inhibitor GPi688 in rat models of hyperglycaemia

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