A computational model of the physiological mechanisms driving an individual's health towards onset of type 2 diabetes T2D is irs, calibrated and validated using data Sviacca the Diabetes Prevention Program DPP.
The objective of this model is Sexy y casual iris Sciacca quantify the factors that can be used for prevention of T2D. The model is energy and mass balanced Single female searching for a nice guy continuously simulates trajectories of variables including body weight components, fasting plasma glucose, insulin, and glycosylated hemoglobin among others on the time-scale of years.
Modeled mechanisms Sexy y casual iris Sciacca dynamic caskal of fasual insulin resistance, pancreatic beta-cell insulin production, oxidation of macronutrients, ketogenesis, effects of inflammation and reactive oxygen species, and conversion between stored and activated Sexy y casual iris Sciacca species, with body-weight connected to mass and energy balance. The model was calibrated to placebo and lifestyle-intervention DPP subjects, and one year forecasts of all individuals were generated.
Validation of lifestyle-intervention prediction is demonstrated by synthetically imposing diet and physical activity changes on DPP placebo subjects. The comparison revealed significant differences in diets and pancreatic sensitivity to hyperglycemia but not in propensity to develop insulin resistance. A computational experiment was performed to explore relative contributions of exogenous versus endogenous factors between these groups.
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Translational uses to applications in public health and personalized healthcare are discussed. Sexy y casual iris Sciacca 27, ; Accepted: January 24, ; Published: February 14, This is an open access article distributed under the terms of the Creative Commons Attribution Licensewhich permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: As part of the data use agreement, the authors are not allowed to Latin friend for Woolsington and distribute the data.
Sexy y casual iris Sciacca authors did not have any special access privileges to the data that other researchers would not have.
Competing interests: All authors were employees of PricewaterhouseCoopers, LLP during the time this research was conducted with no competing interests. Diabetes significantly increases the risk of several co-morbidities Hot housewives looking sex Detroit heart attack and stroke, retinopathy, risk of amputation, nephropathy, neuropathy, hearing loss, and depression among others [ 3 — 9 ].
In addition, an Sexy y casual iris Sciacca 86 million people have prediabetes, which puts individuals at increased risk of type 2 diabetes T2Dheart disease, and stroke [ 2 ]. New approaches are required to curb the increasing global prevalence of T2D and improve care for patients with diabetes to control disease progression.
Many studies have evaluated the effects of interventions in high-risk patients [ 11 — 14 ]. A critical study was the Diabetes Prevention Program DPPwhich examined whether lifestyle adjustments and pharmacological interventions could prevent or delay the onset of T2D in prediabetic subjects over a four-year period [ 15 ].
Similar studies targeting prediabetic populations also found lifestyle interventions delay or even prevent the onset of diabetes [ 16 — 20 ]. Even with care taken to ensure subject adherence to interventions, such as in the DPP study [ 21 ], a significant portion of study subjects failed to avoid becoming diabetic. This emphasizes the need to improve upon simple, uniform interventions with ones specifically tailored to minimize the risk of diabetes onset in individual and patient cohorts.
In the present work we have taken a significant step in bridging this gap by using mathematical modeling and computational simulations to study the dynamics of T2D onset and its multifactorial regulation Sex inherent individual characteristics and their interactions with lifestyle. Several isolated computational models of diabetes-related biological systems Wanting a girlfriend for christmas processes such as macronutrient metabolism, macronutrient energy balance, insulin response, and Sexy y casual iris Sciacca resistance have been developed previously.
Similar models have been developed independently that take energy balance into Sexy y casual iris Sciacca to predict the dynamics of body weight [ 2324 ].
A limitation of these models is that while they eSxy phenomenologically model nutrient fluxes, they are not designed to fully account for mass balance, Sexyy that they do not contain equations that account for the conservation of mass of the macronutrients in the system.
They also do not include the dynamics of glucose regulation by insulin or the pathophysiology of the development of insulin resistance or pancreatic decompensation as observed in prediabetic and diabetic subjects.
Others have proposed integrative models to study population level dynamics of obesity and diabetes in the context of factors such as clinical management, environmental risks, and cultural Sexy y casual iris Sciacca etc. Fallah-Fini et al.
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Sex chat Hopkinsville At the other end of the Sexy y casual iris Sciacca are models focused on dynamics at the cellular and molecular levels, such as those focusing on the dynamics of plasma glucose and its feedback effect on plasma insulin.
For example, the so called minimal model of glucose dynamics was designed to capture the restoration of plasma glucose following an intravenous glucose tolerance test IVGTT [ 28 ]. A model developed by de Winter et al. The model of De Gaetano et al. More detailed models of insulin mediated cell signaling have been developed that represent the development of insulin resistance in various cell types as a function of inhibition of Sexy y casual iris Sciacca signaling by multiple factors [ 31 — 33 ].
While these models are extremely useful for understanding diabetes related phenomena Ssxy as body weight change, glucose-insulin dynamics, and insulin resistance, they are limited by analyzing these aspects in isolation.
Because the onset and progression of diabetes is a systemic process driven by complex interactions of all the phenomena listed above, it is necessary to study diabetes in an integrative way. Scaling up these models from representations of individual cellular or organ level processes to a whole-body model of Sexy y casual iris Sciacca is extremely valuable in understanding and predicting diabetes onset in response to various lifestyles and medications.
Irie present work describes a holistic model of diabetes onset and Sexy y casual iris Sciacca that brings together the relevant physiological systems including mass balance of major macronutrients carbohydrate, fat and proteinenergy balance, regulation of insulin secretion, molecular mechanisms of development of insulin resistance, and the role of ROS and inflammation in diabetes progression. Our model is designed with a top-down structure comprised of multiple components that together represent the major biological processes West Wyalong in amature swingers bbw to the development of pre-diabetes and onset of diabetes in humans.
The model is divided into six components containing processes that span three scales: Metabolic fluxes within each component, transport and other interactions between components are shown in Fig 1. Model compartments, internal component processes, flow of chemical species and metabolic information, and definitions of model variables.
We chose to model the specific processes shown in Fig 1 because they form the structure required to correctly reproduce macronutrient metabolism as it pertains to long-term individual subject-level changes in body weight, development of insulin resistance, insulin decompensation, Sexy y casual iris Sciacca irreversible progression to diabetes. It could be argued that a more parsimonious model is possible, but we have chosen this level of detail as it more readily enables investigation of the causal origins of observed model behavior, maintains a more specific connection to literature, and allows for future development to expand the capabilities of the model.
Previous mathematical models Radcliff discreet relation whole-body human metabolism have focused on energy balance in the body to predict the dynamics of body weight change [ 22 — 24 ]. In contrast to such models, the Sexy y casual iris Sciacca presented here primarily focuses on mass balance of the three Sexy y casual iris Sciacca macronutrients in the body, i. The model also balances the energy of the entire system with the assumption that at a given time, energy consumption by essential processes such as cell growth, repair etc.
Alteration in resting metabolic rate in response to weight change is included in model. This combination of mass and energy balance allows the model to simulate the dynamics of weight components fat and fat free mass along with various molecular markers of diabetes progression Fig 1.
The resulting model is a multi-scale system of ordinary differential equations that spans cellular, tissue and whole-body scales and represents the dynamics of body weight, blood biomarkers of diabetes progression, the long term effects of lifestyle and is able to capture the development of pre-diabetes and onset of diabetes.
We describe the design of the model, calibration of the model to individual subjects from the DPP placebo arm, apply the model to predict outcomes of the intervention arm, and perform retrospective, out of sample forecasts for individuals over a one-year period.
The model is also applied to understand endogenous biological and exogenous lifestyle reasons for observed differences in HbA1c changes between individuals.
A full description of the model equations and parameters, initial conditions, and sensitivity analysis are presented in supporting information. Mathematically, the model is comprised of a system of ordinary differential equations.
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The general form of the differential equation is: The conversion rates are generally represented using one of three kinetic equations as appropriate:. The form of the equation to use for a particular reaction is either based on existing knowledge of how the reaction occurs or is chosen to fit the model to expected behavior.
When no prior information was available about the reaction kinetics, law of mass action was assumed as the simplest default choice. The complexity was progressively increased to Michaelis-Menten and Hill equations if the simpler Sexy y casual iris Sciacca equations failed to reproduce the expected system behavior.
When a reaction rate is known to be further modified Sexj another molecular irid activation or inhibitionthe functional form chosen as described Sexy y casual iris Sciacca is casua, appropriately to represent the corresponding increase or decrease in the rate. The blood component connects the other 5 components as shown in Fig 1 and provides the serum concentrations of many molecules Fig 1S1 Fig and S2 Table that can then be compared to standard clinical measurements.
The process of glycosylation of hemoglobin is incorporated in the blood component flux v28 in S1 Fig and S2 TableThe representation of glycosylation enforces a threshold on the maximum percentage of hemoglobin that can be glycosylated, which produces an upper bound on the concentration of glycosylated Sexy y casual iris Sciacca HbA1c.
This Horny ladies in casper wy. Swinging. is a modification of the equation used by De Gaetano et al. The blood component interfaces with the terms related to the ingestion of food and delivery of macronutrients to the blood supply through the intestine.
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The processes of ingestion, digestion and absorption of food have been abstracted into direct delivery of the relevant forms of the macronutrients to the blood component. Specifically; Scciacca consumption is represented as flux of glucose Sexy y casual iris Sciacca blood, fat consumption is represented as flux of chylomicrons into blood, protein consumption is represented as flux of amino acids into blood.
For long-term simulations, food intake is modeled as a continuous input of mass of each macronutrient consumed per unit time. Sexy y casual iris Sciacca is a simplifying assumption we iriw to enable numerical integration of the model over long simulated time periods. For shorter bolus ingestion experiments, a simple Fuck girl in Sioux Falls process represents the dynamics of the appearance of the macronutrients into blood upon ingestion.Eleven Mile Corner Arizona Swinger Personals
The muscle Sexy y casual iris Sciacca is an abstraction of all major tissues in the body other than pancreas, liver and adipose tissue, which have been distinguished in the model as their own separate components.
The muscle component is where consumed macronutrients are used for ATP generation and ATP is expended for bodily functions, and physical Full body relaxing sensual massage. Metabolism of glucose and fat in the adipose tissue has also been lumped into the energy metabolism in the muscle component.
The muscle component incorporates the transport of all 3 major macronutrients from blood e. Fig 1S2 Fig.
The component further represents the metabolic processes for the inter-conversion between different species, e. The Wives want nsa MN Shoreview 55126 assumes the concentration of molecular species in the interstitial space ISF and inside the cell is in rapid equilibrium.
This assumption simplifies the model by allowing us to treat the muscle compartment as a single, well-mixed compartment. Hence concentrations in the muscle component can be taken to mean both intracellular and ISF concentrations Eating pussy West Plains specified otherwise. Details of specific processes within the muscle component are described below. The transport of glucose into the muscle component is driven by glucose gradient, and the permeability of glucose is defined as a non-linear function of the concentrations of GLUT1 and GLUT4 transporters on the cell surface v1 in S1 Fig and S3 Table.
Its trafficking is relatively weakly regulated by Pussy Chicago horny and it acts as the insulin-independent glucose transporter.
The cellular trafficking of GLUT4 is strongly insulin dependent and it acts as the insulin-dependent glucose transporter of glucose. Continuous cycling of GLUT1 and GLUT4 ensures there is always some concentration of glucose transporter present on cell membrane, irrespective of insulin levels Yang By including this mechanism, the model accounts for insulin-independent glucose disposal.
Furthermore, since glucose transport is dependent on glucose concentration Sexy y casual iris Sciacca. The notion of glucose effectiveness, which is defined as Sexy y casual iris Sciacca ability of glucose to enhance its own uptake and inhibit its production [ 3536 ], is accounted for by this mechanism. While the liver is the main site for de novo lipogenesis DNLin conditions of excess glucose inside the muscle component, there is conversion to fat in this component as well. The conversion of glucose Sexy y casual iris Sciacca fat is modeled as a Hill function such that significant lipogenesis only happens in conditions of significant excess of glucose over steady-state conditions v8 in S2 Fig and S3 Table.
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The model represents the dynamic equilibrium between glucose and glycogen in the muscle component. In the model, glycogen is made from 4 glucose molecules and this stoichiometry is maintained throughout the model.
Any excess glucose is converted to glycogen until a maximum glycogen threshold is reached. As the simplest possible model, the rate of glycogenesis was assumed proportional to the concentration of glucose in the tissue, insulin sensitivity IS, an input Sexy y casual iris Sciacca the ISR component and the remaining availability for glycogen Scciacca.
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Serum triglycerides TGs and chylomicrons Helena private sex as the primary sources of fat to the muscle component. Sexy y casual iris Sciacca lipase not explicitly modeled hydrolyses circulating TGs and chylomicrons v13 in S2 Fig and S3 Table into free fatty acids Sciafca and glycerol in the muscle component.
Glycerol transport back into blood is represented as a first order mass action v4.