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A Generic Integrated Physiologically based Whole-body Model of the Glucose-Insulin-Glucagon Regulatory System.

ABSTRACT: Models of glucose metabolism are a valuable tool for fundamental and applied medical research in diabetes. Use cases range from pharmaceutical target selection to automatic blood glucose control. Standard compartmental models represent little biological detail, which hampers the integration of multiscale data and confines predictive capabilities. We developed a detailed, generic physiologically based whole-body model of the glucose-insulin-glucagon regulatory system, reflecting detailed physiological properties of healthy populations and type 1 diabetes individuals expressed in the respective parameterizations. The model features a detailed representation of absorption models for oral glucose, subcutaneous insulin and glucagon, and an insulin receptor model relating pharmacokinetic properties to pharmacodynamic effects. Model development and validation is based on literature data. The quality of predictions is high and captures relevant observed inter- and intra-individual variability. In the generic form, the model can be applied to the development and validation of novel diabetes treatment strategies.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e65; doi:10.1038/psp.2013.40; published online 14 August 2013.

SUBMITTER: Schaller S

PROVIDER: S-EPMC3828004 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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A Generic Integrated Physiologically based Whole-body Model of the Glucose-Insulin-Glucagon Regulatory System.

Schaller S S Willmann S S Lippert J J Schaupp L L Pieber T R TR Schuppert A A Eissing T T

CPT: pharmacometrics & systems pharmacology 20130814

Models of glucose metabolism are a valuable tool for fundamental and applied medical research in diabetes. Use cases range from pharmaceutical target selection to automatic blood glucose control. Standard compartmental models represent little biological detail, which hampers the integration of multiscale data and confines predictive capabilities. We developed a detailed, generic physiologically based whole-body model of the glucose-insulin-glucagon regulatory system, reflecting detailed physiolo ...[more]

PMID: 23945606

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Project description:Background: Precise and dynamic blood glucose regulation is paramount for both diagnosing and managing diabetes. Continuous glucose monitoring (CGM) coupled with insulin pumps forms an artificial pancreas, enabling closed-loop control of blood glucose levels. Indeed, this integration necessitates advanced micro-nano fabrication techniques to miniaturize and combine sensing and delivery modules on a single electrode. While microneedle technology can mitigate discomfort, concerns remain regarding infection risk and potential sensitivity limitations due to their short needle length. Methods: This study presents the development of an integrated electronic/fluidic microneedle patch (IEFMN) designed for both glucose sensing and insulin delivery. The use of minimally invasive microneedles mitigates nerve contact and reduces infection risks. The incorporation of wired enzymes addresses the issue of "oxygen deprivation" during glucose detection by decreasing the reliance on oxygen. The glucose-sensing electrodes employ wired enzyme functionalization to achieve lower operating voltages and enhanced resilience to sensor interference. The hollow microneedles' inner channel facilitates precise drug delivery for blood glucose regulation. Results: Our IEFMN-based system demonstrated high sensitivity, selectivity, and a wide response range in glucose detection at relatively low voltages. This effectively reduced interference from both external and internal active substances. The microneedle array ensured painless and minimally invasive skin penetration, while wired enzyme functionalization not only lowered sensing potential but also improved glucose detection accuracy. In vivo, experiments conducted in rats showed that the device could track subcutaneous glucose fluctuations in real-time and deliver insulin to regulate blood glucose levels. Conclusions: Our work suggests that the IEFMN-based system, developed for glucose sensing and insulin delivery, exhibits good performance during in vivo glucose detection and drug delivery. It holds the potential to contribute to real-time, intelligent, and controllable diabetes management.

Project description:BackgroundPolycystic ovary syndrome (PCOS) is a highly prevalent endocrine-metabolic disorder associated with insulin resistance (IR). In IR states, non-insulin-mediated glucose uptake (NIMGU) may increase to compensate for declining insulin-mediated glucose uptake (IMGU), although this does not appear to be the case in PCOS. The underlying molecular mechanisms for this deficiency remain unclear.ObjectivesTo compare adipocyte glucose transporter 1 and 4 (GLUT-1 and GLUT-4) gene expression in PCOS women and matched controls, and to determine whether changes in GLUT-1 and GLUT-4 are associated with concomitant alterations in whole-body glucose uptake.Research design and methodsIn this prospective cross-sectional study, 23 women with PCOS (by NIH 1990 criteria) and 23 matched controls were studied for subcutaneous abdominal adipocyte GLUT-1 and GLUT-4 mRNA expression (by real-time PCR), and basal whole-body IR (by HOMA-IR) and insulin secretion (by HOMA-β%). A subset of six PCOS women and six matched controls also underwent a mFSIVGTT to determine dynamic state glucose uptake (by insulin sensitivity index [Si] and glucose effectiveness [Sg]) and insulin secretion (by the acute insulin response to glucose [AIRg] and the disposition index [Di]).ResultsFor similar adiposity (BMI and waist-hip ratio), PCOS women tended to have higher HOMA-IR and lower Di and Si, and higher HOMA-β% and lower GLUT-4 than controls, while GLUT-1 was similar. GLUT-1 was positively associated with Sg (reflecting NIMGU) and GLUT-4 positively with Si (reflecting IMGU). GLUT-4 was associated negatively with HOMA-IR and HOMA-β% and positively with Di for the entire cohort but not with AIRg. Both GLUT-1 and GLU-4 were negatively associated with BMI, but not with each other.ConclusionOur results suggest that IR secondary to a lower IMGU and enhanced insulin secretion in PCOS is in part attributable to a reduction in adipocyte GLUT-4 expression that is not accompanied by a compensatory increase in GLUT-1 expression.

Project description:Type 2 diabetes (T2D) is a pathophysiology that is characterized by insulin resistance, beta- and alpha-cell dysfunction. Mathematical models of various glucose challenge experiments have been developed to quantify the contribution of insulin and beta-cell dysfunction to the pathophysiology of T2D. There is a need for effective extended models that also capture the impact of alpha-cell dysregulation on T2D. In this paper a delay differential equation-based model is developed to describe the coupled glucose-insulin-glucagon dynamics in the isoglycemic intravenous glucose infusion (IIGI) experiment. As the glucose profile in IIGI is tailored to match that of a corresponding oral glucose tolerance test (OGTT), it provides a perfect method for studying hormone responses that are in the normal physiological domain and without the confounding effect of incretins and other gut mediated factors. The model was fit to IIGI data from individuals with and without T2D. Parameters related to glucagon action, suppression, and secretion as well as measures of insulin sensitivity, and glucose stimulated response were determined simultaneously. Significant impairment in glucose dependent glucagon suppression was observed in patients with T2D (duration of T2D: 8 (6-36) months) relative to weight matched control subjects (CS) without diabetes (k1 (mM)-1: 0.16 ± 0.015 (T2D, n = 7); 0.26 ± 0.047 (CS, n = 7)). Insulin action was significantly lower in patients with T2D (a1 (10 pM min)-1: 0.000084 ± 0.0000075 (T2D); 0.00052 ± 0.00015 (CS)) and the Hill coefficient in the equation for glucose dependent insulin response was found to be significantly different in T2D patients relative to CS (h: 1.4 ± 0.15; 1.9 ± 0.14). Trends in parameters with respect to fasting plasma glucose, HbA1c and 2-h glucose values are also presented. Significantly, a negative linear relationship is observed between the glucagon suppression parameter, k1, and the three markers for diabetes and is thus indicative of the role of glucagon in exacerbating the pathophysiology of diabetes (Spearman Rank Correlation: (n = 12; (-0.79, 0.002), (-0.73,.007), (-0.86,.0003)) respectively).

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A Generic Integrated Physiologically based Whole-body Model of the Glucose-Insulin-Glucagon Regulatory System.

Publications

A Generic Integrated Physiologically based Whole-body Model of the Glucose-Insulin-Glucagon Regulatory System.

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