Blood Glucose Levels in Rhesus Monkeys (Macaca mulatta) and Cynomolgus Macaques (Macaca fascicularis) under Moderate Stress and after Recovery

Лапин, Б. А.; Gvozdik, T. E.; Klots, I. N.

doi:10.1007/s10517-013-1986-7

Cited by 11 publications

(10 citation statements)

References 7 publications

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“…There were no outliers (ROUT method, Q = 1%) and no severe incidents of hypoglycemia in these normal, healthy monkeys ( Fig 5c ). The lowest detected concentration (73 mg/dL for subject 3 at 0.5 h) still falls well within the normal fed blood glucose range for cynomolgus macaques 50 . Assuming a similar bioavailability across species and using power laws of allometric scaling, this data suggests that our injectable GLP1-ELP opt depots could provide prolonged release for 3 weeks of glycemic control in humans.…”

Section: Resultssupporting

confidence: 52%

One-week glucose control via zero-order release kinetics from an injectable depot of glucagon-like peptide-1 fused to a thermosensitive biopolymer

et al. 2017

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Stimulation of the glucagon-like peptide-1 (GLP1) receptor is a useful treatment strategy for type 2 diabetes because of pleiotropic effects, including the regulation of islet hormones and the induction of satiety. However, the native ligand for the GLP1 receptor has a short half-live owing to enzymatic inactivation and rapid clearance. Here, we show that a subcutaneous depot formed after a single injection of GLP1 recombinantly fused to a thermosensitive elastin-like polypeptide results in zero-order release kinetics and circulation times of up to 10 days in mice and 17 days in monkeys. The optimized pharmacokinetics leads to 10 days of glycemic control in three different mouse models of diabetes, as well as to the reduction of glycosylated hemoglobin levels and weight gain in ob/ob mice treated once weekly for 8 weeks. Our results suggest that the optimized GLP1 formulation could enhance therapeutic outcomes by eliminating peak-and-valley pharmacokinetics and improving overall safety and tolerability. The design principles that we established should be broadly applicable for improving the pharmacological performance of other peptide and protein therapeutics.

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Section: Resultssupporting

confidence: 52%

One-week glucose control via zero-order release kinetics from an injectable depot of glucagon-like peptide-1 fused to a thermosensitive biopolymer

et al. 2017

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“…For example, in a macaque model of diabetes, physical restraint of non-human primates for blood collection activates a stress response that causes rapid changes in blood glucose levels 75,76 . Habituation to the procedure or use of voluntary handling techniques based on positive reinforcement training can allow researchers to obtain blood with a comparatively minimal stress response; these measures will more closely reflect the animal's biology, rather than the intensity of the aversive experience itself [75][76][77] .…”

Section: Reviewmentioning

confidence: 99%

Introducing Therioepistemology: the study of how knowledge is gained from animal research

et al. 2017

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We are honored to write the opening article of this focus issue of Lab Animal. This focus issue could not occur at a more important time for biomedical research and the use of animals in science in general. The progressive worsening of success rates in human trials (currently 1 in 9 drugs entering human trials will succeed) 1-4 , combined with the explosion of interest in the reproducibility crisis 5-8 and the recognition that most drugs fail in human trials due to insufficient efficacy 1,2,4 , has led to a growing suspicion that the failure of translation from animal work to human outcomes may in some way reflect issues in animal research itself 5-19 -after all, every drug that fails in humans "worked" in an animal model. Indeed pharmaceutical companies continue to disinvest in internal animal R&D, a trend begun in the last decade, passing on the cost and risk to academia and startups 5,20 . Even this approach is not foolproof as pharmaceutical companies often cannot replicate the results of published work from academia 5,8,13 . Accordingly, there is a growing trend to focus on human, not animal, work for basic discovery 17 .Discarding animal research entirely is not the answer. When properly used, animal models have incredible value, not least the ability to follow biomarkers from birth to disease onset in a year or less (in the case of mice), which is impossible in humans 17,18 . There are patterns and principles that can help us identify models and results that are more or less likely to translate, and there are also easily realized, simple changes in the execution of animal work that will inherently improve translation [16][17][18] . This isn't a new concept; looking back over the last 10-15 years we can see many authors have been candid about the merits, strengths, weaknesses, reproducibility, and translatability of various animal models 1,2,[4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] . Our goal with this article is to unite the common themes in this broader emerging literature and this special issue.Thus, the central point is that we (i.e., refs. 17,18,26-28,39,41) do not represent a voice in the wilderness, but one voice in a chorus and that this emerging literature 1,2,[4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]42,43 reflects a nascent discipline which can be codified as the study of how knowledge is gained from animal research. We propose the title "Therioepistemology" This focus issue of Lab Animal coincides with a tipping point in biomedical research. For the first time, the scale of the reproducibility and translatability crisis is widely understood beyond the small cadre of researchers who have been studying it and the pharmaceutical and biotech companies who have been living it. Here we argue that an emerging literature, including the papers in this focus issue, has begun to congeal around a set of recurring themes, which themselves represent a paradigm shift. This paradigm shift can be c...

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“…The primary outcome measure in diabetes studies is often a stress sensitive metabolic parameter (e.g. blood glucose) so refined animal handling techniques are imperative ( Lapin et al, 2013; Shirasaki et al, 2013;Gartner et al, 1980 ). Nonhuman primates are extensively used in to study β-cell replacement strategies (e.g.…”

Section: Rs Use To Reduce Harm To Animals and Increase Translationalmentioning

confidence: 99%

The multifactorial role of the 3Rs in shifting the harm-benefit analysis in animal models of disease

Graham

Prescott

2015

European Journal of Pharmacology

153

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Ethics on animal use in science in Western society is based on utilitarianism, weighing the harms and benefits to the animals involved against those of the intended human beneficiaries. The 3Rs concept (Replacement, Reduction, Refinement) is both a robust framework for minimizing animal use and suffering (addressing the harms to animals) and a means of supporting high quality science and translation (addressing the benefits). The ambiguity of basic research performed early in the research continuum can sometimes make harm-benefit analysis more difficult since anticipated benefit is often an incremental contribution to a field of knowledge. On the other hand, benefit is much more evident in translational research aimed at developing treatments for direct application in humans or animals suffering from disease. Though benefit may be easier to define, it should certainly not be considered automatic. Issues related to model validity seriously compromise experiments and have been implicated as a major impediment in translation, especially in complex disease models where harms to animals can be intensified. Increased investment and activity in the 3Rs is delivering new research models, tools and approaches with reduced reliance on animal use, improved animal welfare, and improved scientific and predictive value.

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Blood Glucose Levels in Rhesus Monkeys (Macaca mulatta) and Cynomolgus Macaques (Macaca fascicularis) under Moderate Stress and after Recovery

Cited by 11 publications

References 7 publications

One-week glucose control via zero-order release kinetics from an injectable depot of glucagon-like peptide-1 fused to a thermosensitive biopolymer

One-week glucose control via zero-order release kinetics from an injectable depot of glucagon-like peptide-1 fused to a thermosensitive biopolymer

Introducing Therioepistemology: the study of how knowledge is gained from animal research

The multifactorial role of the 3Rs in shifting the harm-benefit analysis in animal models of disease

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