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Modeling the Diseas...
Modeling the Disease Progression from Healthy to Overt Diabetes in ZDSD Rats
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- Choy, Steve (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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- de Winter, Willem (författare)
- Janssen Res & Dev, Janssen Prevent Ctr, Leiden, Netherlands.
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- Karlsson, Mats O. (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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visa fler...
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- Kjellsson, Maria C. (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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visa färre...
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(creator_code:org_t)
- 2016-05-31
- 2016
- Engelska.
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Ingår i: AAPS Journal. - : Springer Science and Business Media LLC. - 1550-7416. ; 18:5, s. 1203-1212
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Studying the critical transitional phase between healthy to overtly diabetic in type 2 diabetes mellitus (T2DM) is of interest, but acquiring such clinical data is impractical due to ethical concerns and would require a long study duration. A population model using Zucker diabetic Sprague-Dawley (ZDSD) rats was developed to describe this transition through altering insulin sensitivity (IS, %) as a result of accumulating excess body weight and beta-cell function (BCF, %) to affect glucose-insulin homeostasis. Body weight, fasting plasma glucose (FPG), and fasting serum insulin (FSI) were collected biweekly over 24 weeks from ZDSD rats (n = 23) starting at age 7 weeks. A semi-mechanistic model previously developed with clinical data was adapted to rat data with BCF and IS estimated relative to humans. Non-linear mixed-effect model estimation was performed using NONMEM. Baseline IS and BCF were 41% compared to healthy humans. BCF was described with a non-linear rise which peaked at 14 weeks before gradually declining to a negligible level. A component for excess growth reflecting obesity was used to affect IS, and a glucose-dependent renal effect exerted a two- to sixfold increase on the elimination of glucose. A glucose-dependent weight loss effect towards the end of experiment was implemented. A semi-mechanistic model to describe the dynamics of glucose and insulin was successfully developed for a rat population, transitioning from healthy to advanced diabetes. It is also shown that weight loss can be modeled to mimic the glucotoxicity phenomenon seen in advanced hyperglycemia.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
Nyckelord
- disease progression
- semi-mechanistic model
- type 2 diabetes
- weight
- ZDSD rats
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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