Modelo Matematico Insulina

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c o m p u t e r m e t h o d s a n d p r o g r a m s i n b i o m e d i c i n e x x x ( 2 0 1 1 ) xxxxxx
journal homepage: www.intl.elsevierhealth.com/journals/cmpb
Identication of an integrated mathematical model of standard oral glucose tolerance test for characterization of insulin potentiation in health
Roberto Burattini , Micaela Morettini
Department of Information Engineering, Polytechnic University of Marche, Via Brecce Bianche, 60131 Ancona, Italy
a r t i c l e
Article history:
i n f o
a b s t r a c t
Two new formulations, respectively denominated INT M1 and INT M2, of an integrated mathematical model to describe the glycemic and insulinemic responses to a 75 g oral glucose tolerance test (OGTT) are proposed and compared. The INT M1 assumes a single compartment for the intestine and the derivative of a power exponential function for the gastric emptying rate, while, in the INT M2, a nonlinear three-compartment system model is adopted to produce a more realistic, multiphase gastric emptying rate. Both models were implemented in a Matlab-based, two-step procedure for estimation of seven adjustable coefcients characterizing the gastric emptying rate and the incretin, insulin and glucose kinetics. Model behaviour was tested vs. mean plasma glucagon-like peptide 1 (GLP1), glucose-dependent insulinotropic polypeptide (GIP), glucose and insulin measurements from two different laboratories, where glycemic proles observed during a 75 g OGTT were matched in healthy subjects (HC1- and HC2-group, respectively) by means of an isoglycemic intravenous glucose (I-IVG) infusion. Under the hypothesis of an additive effect of GLP-1 and GIP on insulin potentiation, our results demonstrated a substantial equivalence of the two models in matching the data. Model parameter estimates showed to be suitable markers of differences observed in the OGTT and matched I-IVG responses from the HC1-group compared to the HC2-group. Model implementation in our two-step parameter estimation procedure enhances the possibility of a prospective application for individualization of the incretin effect in a single subject, when his/her data are plugged in. 2011 Elsevier Ireland Ltd. All rights reserved.
Received 10 December 2010 Received in revised form 14 May 2011 Accepted 4 July 2011 Keywords: Glucose-insulin system Gastric emptying Oral glucose absorption GIP GLP-1 Incretin effect Parameter estimation
1.
Introduction
Mathematical modelling in the assessment of insulinglucose interactions has a longstanding tradition, and reported models show a wide degree of complexity depending on their purpose. Besides models of minimal complexity, some of which are referred to as minimal models, after Bergman et al. [1], increasing relevance is being assumed by integrated simu-
lation models of the glucose-insulin control system during an oral glucose tolerance test (OGTT) or meal glucose tolerance test (MGTT) to improve knowledge of diabetes pathophysiology and assess the efcacy of hypoglycemic agents in clinical drug development [26]. In this context, a key issue concerns the modelling of glucose transit through the gastrointestinal tract, to describe glucose absorption [79] and the related incretin effect [8,1019], mostly due to the contribution of glucagon-like peptide-1 (GLP-1) and glucose-dependent
Corresponding author. Tel.: +39 071 2204458; fax: +39 071 2204224. E-mail address: r.burattini@univpm.it (R. Burattini). 0169-2607/$ see front matter 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.cmpb.2011.07.002
Please cite this article in press as: R. Burattini, M. Morettini, Identication of an integrated mathematical model of standard oral glucose tolerance test for characterization of insulin potentiation in health, Comput. Methods Programs Biomed. (2011), doi:10.1016/j.cmpb.2011.07.002
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insulinotropic polypeptide (GIP) released in response to nutrient ingestion, which stimulate oral glucose dependent insulin secretion. A promising simulation model of the oral glucose tolerance test, primarily intended to illustrate the importance of incretin within the normal ranges observed clinically in humans, has recently been proposed by Brubaker et al. [4]. Unfortunately, a simple empiric description of the rate of gastric emptying of ingested glucose into the gut, Gempt , constrains the model to the reproduction of glycemia and insulinemia responses to 50 and 100 g oral glucose loads, and does not allow an effective model testing versus experimental data measured during clinical OGTT protocols, which generally consist of the administration of a standard 75 g glucose dose. In its original formulation [4] the model was characterized by fteen parameters, ten of which were given numerical values known a priori from previously reported measurements, thus leaving ve adjustable parameters. However, the lack of a validation against standard OGTT data limits the reliability of the values assumed for these adjustable parameters, thus affecting the predictive capabilities of the model. Based on these considerations, the aim of the present study was to improve the model formulation by incorporating a mathematical description of oral glucose absorption that allows model application to standard OGTT data, such that adjustable model parameters can be better assessed by tting to clinical data. Two competing integrated mathematical models of oral glucose tolerance test, denominated INT M1 and INT M2, respectively, were obtained by incorporating two alternative representations of glucose absorption. The former model incorporates a single compartment for the intestine and the derivative of a power exponential function for the gastric emptying rate [7]. In the latter, a nonlinear threecompartment system model is adopted to produce a more realistic multiphase gastric emptying rate [9]. A comparative analysis of INT M1 and INT M2 behaviour was performed in terms of their ability to reproduce the augmented glucosedependent plasma insulin concentration (generally referred to as incretin-induced insulin potentiation) observed after an OGTT, as it compares with the insulin response to an intravenous glucose infusion given in amount sufcient to match the prole of glucose concentration observed during OGTT (isoglycemic intravenous glucose, I-IVG, infusion) [15,18,19]. Especially, mean data of OGTT and I-IVG responses from two groups of metabolically healthy subjects (here denominated HC1- and HC2-group), respectively reported by Muscelli et al. [18] and Nauck et al. [15], were used to test our models capability to reproduce and interpret differences in essential aspects of insulin potentiation in health observed in the data sets from the two different laboratories.
2.
2.1.
Methods
Model formulation
The model previously proposed by Brubaker et al. [4] to simulate the glycemic and insulinemic responses to a 50 and a 100 g oral glucose load, with explicit incorporation of incretin action, was used as a basis to build-up an integrated model
upon an OGTT protocol consisting of oral administration of a standard 75 g oral glucose load (i.e. 1 g of glucose per kg body weight, BW, administered at time t = 0 min, and standardized to a 75 kg individual). To this aim the description of the oral glucose absorption was modied by incorporating either a one-compartment model [7], denoted as M1, or a three-compartment model [9], denoted as M2. The two versions of our integrated model, the ow diagram of which is depicted in Fig. 1, were denoted as INT M1 when incorporating the M1, and INT M2 when incorporating the M2, respectively. The overall mathematical description is given in the Appendix A. Description, basal values and units for both the INT M1 and the INT M2 variables are given in Table 1. In the absence of measurements of basal hepatic glucose balance, HGBb , the value of 0.77 mmol min1 was deduced from the literature by multiplying the BW of 75 kg times 10.25 103 mmol min1 kg1 determined as the mean of two hepatic glucose balance values per unit BW reported by Bell et al. [20] (and summarized at points 3 and 4 of Table A.1 in [21]) for humans with mean glycemia of 5.28 mmol L1 and mean insulinemia of 10 mU L1 , which are consistent with the mean fasting values of glycemia and insulinemia characterizing our HC1-group (5.4 mmol L1 and 10.2 mU L1 , respectively) and HC2-group (5.5 mmol L1 and 7.6 mU L1 , respectively). Besides the basal values of variables as given in Table 1, and considered that HGBb is treated as a xed parameter, the INT M1 formulation consists of fteen further independent parameters; namely, k3 , k4 , k5 , k6 , k7 , k8 , k9 , p, V, M, , kabs , f, ke and . Instead, the INT M2 is characterized by seventeen parameters, because in this model the ke and characteristic parameters of the monophase waveshape for the rate of gastric emptying (Gempt ; Eq. (A1)) are replaced by the c, b, kmin , and kmax coefcients of the emptying function kempt (qsto ) of Eq. (A10). Quantication of all these parameters was accomplished as follows. The k3 , k4 , k6 , k9 , p and V were assumed as xed and were given numerical values (Table 2) known a priori from observations reported in the literature, as discussed by Brubaker et al. [4]. The kabs , f, b and c parameters pertaining to glucose absorption were also assumed as xed (Table 2). In accordance with the validation studies on glucose-absorption models reported by Dalla Man et al. [9,22], the value of 0.22 min1 was assumed for the rate constant, kabs , of intestinal glucose absorption, while the value of 0.90 was assumed for the fraction, f, of the ingested glucose dose, D, that is actually absorbed. Eventually, the b and c dimensionless coefcients were given the values of 0.85 and 0.25, respectively, thus xing the percentage of the glucose dose, D, for which the emptying function kempt (Eq. (A10)) decreases (b) and subsequently increases (c) at (kmax kmin )/2 [9]. The remaining independent model parameters, denoted as k5 , k7 , k8 , M and , which were assumed as adjustable in the original model of Brubaker et al. [4] and presumably manually adjusted, were considered as free parameters in addition to the ke and in the INT M1 model formulation, and in addition to kmin and kmax in the INT M2 model formulation. One novel aspect of the present work is that these free parameters were automatically estimated by a two step procedure as described in Section 2.3.
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Fig. 1 Flow diagram of our integrated model incorporating either one of two alternative formulations of glucose absorption, denoted as M1 and M2. The M1 representation assumes the derivative of a power exponential function for the gastric emptying rate (Gempt ) of the oral glucose dose (D), and a single compartment for the gut (qgut ). In the M2 conguration, the oral glucose dose enters a two compartment model (qsto1 and qsto2 ) of the stomach, while a gastric emptying function (kempt ), dependent on the total amount of glucose in the stomach (qsto , equal to the sum of qsto1 and qsto2 ), plays a key role in determining the time course of both the rate of emptying of oral glucose load into the gut (Gempt ) and the glucose quantity in the gut compartment (qgut ). In both our integrated model formulations (denominated INT M1 and INT M2, respectively), the Gempt is transmuted by the k5 coefcient into a signal that enters the compartment of plasma incretin (INC). Similarly, qgut is multiplied by the kabs rate constant of intestinal absorption and the f fraction of the intestinal absorption that actually appears into plasma, to predict the RaG rate of glucose absorption from the gut into the mesenteric circulation. This feeds the glucose compartment (G). Solid lines with arrows indicate directional ows. Dashed lines with arrows indicate control actions of incretin (INC) and glucose (G) on post-hepatic insulin secretion, as well as control actions of insulin (I) on hepatic glucose balance (HGB) and glucose delivery to the peripheral tissues.
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Table 1 Description, basal values and units for model variables. Constant
qsto1b qsto2b qgutb Gb Ib INCb HGBb Gemptb RaGb
Description
Amount of glucose in the compartment 1 of stomach. Amount of glucose in the compartment 2 of stomach. Glucose mass in the intestine. Plasma glucose concentration. Plasma insulin concentration. Plasma incretin concentration. Hepatic glucose balance. Rate of emptying of glucose load into the gut. Rate of appearance of glucose in the peripheral circulation.
Value
0 0 0 Fasting measurement Fasting measurement Fasting measurement 0.77 0 0
Units
mmol mmol mmol mmol L1 mU L1 ng L1 mmol min1 mmol min1 mmol min1
In accordance with Dalla Man et al. [9], to favour numerical identiability of the INT M2 model, the constraint k21 = kmax was imposed. After INT M1 and INT M2 model parameter estimation was accomplished, the remaining dependent parameters 1 , 2 , RaINCb , , k1 , and k2 were computed by Eqs. (A11), (A12), (A15), (A17), (A20) and (A21), respectively.
2.2.
Model testing vs. reported experimental data
Our INT M1 and INT M2 model outputs were tested against data of plasma glucagon-like peptide-1 (GLP-1), glucosedependent insulinotropic polypeptide (GIP), glucose and insulin concentration, averaged over two groups of metabolically healthy subjects, here denominated HC1- and HC2group, respectively reported by Muscelli et al. [18] and Nauck et al. [15]. Essentially, the subjects involved in these previous studies underwent two different glucose-challenge protocols. On the rst occasion (OGTT protocol) the subject ingested 75 g of glucose, whereas on the second occasion (I-IVG protocol) an intravenous glucose infusion was given in amount sufcient to match the prole of glucose concentration observed during OGTT [15,18]. An augmented glucose-dependent insulin secretion (insulin potentiation), observed in these circumstances after OGTT, compared to the matched I-IVG infusion, is attributed to the inuence of the so called incretin effect mostly due to the gut-derived incretin hormones, GLP-1 and
GIP, which enhance glucose-dependent insulin secretion by binding to specic receptors on the -cell [2325]. These hormones are released during glucose or meal intake in proportion to nutrient transport across the intestinal epithelium [10], their effect seems to be additive, and they stimulate insulin secretion both at fasting and postprandial plasma glucose level [14]. On this basis, the mean levels of GLP-1 and GIP (expressed in pmol L1 ) reported in [18] for the HC1-group, and in [15] for the HC2-group, were combined as follows to dene an INC(t) signal for each group. First, the reported mean levels of GLP-1 and GIP, expressed in pmol L1 , were converted into ng L1 (conversion factors were: 1 pmol L1 = 3.30 ng L1 for the GLP-1, and 1 pmol L1 = 4.98 ng L1 for the GIP) and, then, for each group the INC(t) signal was determined as the sum of related GLP-1 and GIP. Eventually, this INC(t) signal was used together with the glycemia, G(t), and insulinemia, I(t), data, and the related Gb , Ib and INCb , fasting values, for model parameter estimation by the procedure described in Section 2.3.
2.3.
Parameter estimation procedure
As explained in Section 2.1, the INT M1 and the INT M2 are characterized by seven free parameters, i.e., k5 , k7 , k8 , M, , and ke , the former, and k5 , k7 , k8 , M, , kmin and kmax, the latter. To dene an optimal value for each one of these parameters, a two-step parameter estimation procedure was set-up as follows.
Table 2 Description, values and units for xed INT M1 and INT M2 model parameters. Coefcient
kabs f c b p k3 k4 k6 k9 V
Description
Rate constant of intestinal absorption. Fraction of the intestinal absorption which actually appears into plasma. Glucose dose percentage corresponding to the rst ex point of the kempt (qsto ) function (Eq. (A10)). Glucose dose percentage corresponding to the second ex point of the kempt (qsto ) function (Eq. (A10)). Ratio of non-insulin mediated to insulin mediated glucose uptake (NIMGU/IMGU; Eq. (A19)). Slope of renal glucose clearance. Intercept of renal glucose clearance. Measure of degradation/clearance of incretin. Measure of degradation/clearance of insulin. Volume of distribution.
Value
0.22 0.90 0.25 0.85 2 0.0718 0.717 0.1 0.1 15
Units
min1
L min1 mmol min1 min1 min1 L
Source: Sources of the values given to p, k3 , k4 , k6 , k9 and V are found in Brubaker et al. [4]. Values of kabs , f, c and b are taken from Dalla Man et al. [9,22].
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2.4. Insulin potentiation
The rst step was to estimate the k7 parameter by running either the INT M1 and the INT M2 to t mean plasma insulin concentrations from the I-IVG protocol. To this aim, Gempt (and, with it, the dynamic component of plasma incretin inow in Eq. (A14)) was set to zero, while the incretin level was maintained at the basal value, INCb , and the glucose prole matched to that measured during OGTT in the HC1- and HC2-group, respectively, was used as model input instead of the description by Eq. (A18). Under these conditions, glucose absorption is not involved, so that k7 (Eq. (A16)) is the only one free parameter that remains to be estimated from tting the model predicted I(t) to I-IVG insulin data. In a subsequent step, the k7 estimate was lled into the INT M1 and the INT M2, which were run to generate incretin, glycemia and insulinemia responses to a 75 g OGTT, to be simultaneously tted to the OGTT data (corresponding to each I-IVG), in order to estimate the six remaining unknown parameters (k5 , k8 , M, , ke and ) of the INT M1, as well as the six remaining unknown parameters (k5 , k8 , M, , kmin , and kmax ) of the INT M2. All model formulations were implemented in MatlabSimulink environment. Data t and parameter estimation were accomplished by means of a weighted least squares (WLS) procedure [26]. The following sum of square error (SSE) expression was used to t the model predicted I-IVG insulin output at the i-th instant, Im (ti ), to the corresponding insulin measurement, I(ti ):
In accordance with Nauck et al. [11], the quantity of -cell secretory response evoked by factors other than glucose itself (insulin potentiation) was deduced from the difference in integrated incremental responses (over basal) of insulinemia between OGTT and matched I-IVG protocols. This insulin potentiation, IP, can be quantied as the percentage of the OGTT response by the equation:
IP% =
AUCIOGTT AUCII-IVG 100 AUCIOGTT
(3)
where AUCIOGTT and AUCII-IVG represent the area under the curve of incremental insulin concentration over the OGTT and the matched I-IVG duration, respectively, according to the trapezoidal rule.
3.
Results
SSEI-IVG =
=1
Im (ti ) I(ti )
Ii
(1)
The following SSE expression was subsequently used for simultaneous t of model predicted OGTT incretin, INCm (ti ), glycemia, Gm (ti ), and insulinemia, Im (ti ), outputs at the i-th instant, to the corresponding incretin, INC(ti ), glycemia, G(ti ), and insulinemia, I(ti ), measurements:
SSEOGTT =
=1
INCm (ti ) INC(ti )

INCi 2
Gm (ti ) G(ti )
Gi
Im (ti ) I(ti )
Ii
(2)
The weights, INCi , Gi , Ii , were assumed equal to 5.5%, 1.5% and 4% of INC(ti ), G(ti ) and I(ti ), respectively, under the assumption of normal distribution with zero mean for the measurement errors [18,26]. The goodness of t was evaluated by calculation of the root-mean-square errors, RMSEI-IVG = SSEI-IVG /N and RMSEOGTT = SSEOGTT /3N Precision of all parameter estimates was expressed as percent coefcient of variation: CV(pi )% = SDpi /pi 100, where pi is the i-th component of the model parameters vector and SDpi is the standard deviation of pi , which is calculated as the square root of the diagonal terms of the inverse of the Fisher information matrix.
Mean fasting values of Gb , Ib , and INCb were 5.4 mmol L1 , 10.2 mU L1 , and 145 ng L1 , respectively, for the HC1-group, and 5.5 mmol L1 , 7.6 mU L1 , and 90 ng L1 , respectively, for the HC2-group. Fitting the INT M1 and INT M2 outputs (dash-dot line in Fig. 2C and F) to mean insulinemia data from OGTTmatched I-IVG protocols, reported for the HC1-group and HC2-group (open circles in Fig. 2C and F, respectively), yielded the RMSEI-IVG and the estimates of k7 given in Table 3 for the former model and in Table 4 for the latter. After feeding the INT M1 and the INT M2 with the k7 values obtained from the previous step, the INC(t), G(t) and I(t) responses to a 75 g OGTT were generated and tted to incretin, glycemia and insulinemia data from OGTT protocols corresponding to each I-IVG, thus estimating the k5 , k8 , M, , ke and values reported in Table 3 for the INT M1, and the k5 , k8 , M, , kmin and kmax values reported in Table 4 for the INT M2. Eventually, computation of 1 (Eq. (A11)), 2 (Eq. (A12)), RaINCb (Eq. (A15)), (Eq. (A17)), k1 (Eq. (A20)) and k2 (Eq. (A21)) yielded the values given in Table 5. Fig. 2 displays the quality of data t obtained from applying the INT M1 (dashed line) and the INT M2 (solid line) to mean OGTT data from the HC1-group (panels AC), and the HC2-group (panels DF). Values of RMSEOGTT are reported in Table 3 for the INT M1 and in Table 4 for the INT M2. Fig. 3 displays the time course of the Gempt and RaG proles predicted by the INT M1 (dashed line) and the INT M2 (solid line) for the HC1-group (panels A and B, respectively) and the HC2-group (panels C and D, respectively). The grey area in panels B and D represents the range of variability of RaG , measured with the multiple tracer, tracer-to-tracee clamp technique during OGTT as reported by Dalla Man et al. [9]. Values of the insulin potentiation index, IP%, computed by Eq. (3) from OGTT and matched I-IVG insulinemia outputs produced by the INT M1 and INT M2 models are compared in Table 6 with the corresponding IP% values computed from mean insulinemia data of the HC1- and HC2-group.
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A
500
HC1
D
500 400 300 200 100
HC2
INC(t) (ngL-1)
300 200 100 0 30 60 90 120 150 180 210 240
INC(t) (ngL-1)
400
30
60
90
120 150 180 210 240
Time (min)
Time (min)
B
G(t) (mmolL-1)
12 11 10 9 8 7 6 5 4 0 30 60 90 120 150 180 210 240
E
G(t) (mmolL-1)
12 11 10 9 8 7 6 5 4 0 30 60 90 120 150 180 210 240
Time (min)
Time (min)
C
I(t) (mUL-1)
120 100
120 100
I(t) (mUL-1)
80 60 40 20 0 0 30 60 90 120 150 180 210 240
80 60 40 20 0 0 30 60 90 120 150 180 210 240
Time (min)
Time (min)
Fig. 2 Mean data of plasma incretin (closed triangles in panels A and D), glucose (closed squares in panels B and E) and insulin (closed circles in panels C and F) concentrations in response to 75 g oral glucose challenge in the HC1-group (left hand column) and the HC2-group (right hand column) are matched by the proles of INC(t), G(t), and I(t) outputs of the INT M1 (dashed lines) and the INT M2 (solid lines) models after free parameter optimization. Open circles in panels C and F are mean plasma insulin concentration data from the HC1- and HC2-group, respectively, measured after the glycemic proles observed following glucose ingestion (OGTT) were matched by means of an isoglycemic intravenous glucose (I-IVG) infusion (open squares in panels B and E). The dash-dot line in panels C and F describes the best tting I-IVG insulin output provided by both the INT M1 and the INT M2 model.
4.
Discussion
This work yields an improved formulation of a mathematical model previously proposed by Brubaker et al. [4] to simulate the glycemia and insulinemia responses to 50 and 100 g oral glucose administration, by explicitly incorporating the incretin effect. The incretin response, INC(t), is thought to be a direct effect of the rate of emptying of ingested glucose into the gut, Gempt (t), through a zero-order transfer function, with k5 gain, between the Gempt and the dynamic component
of plasma incretin inow (Eq. (A14)). An improved description of intestinal glucose absorption in response to 75 g OGTT, was accomplished here by replacing the previously proposed empirical description, restricted to 50 and 100 g glucose challenge [4], with either a one-compartment model (M1 in Fig. 1) and a three-compartment model (M2 in Fig. 1), thus giving rise to two integrated models denominated INT-M1 and INT-M2, respectively. Besides the k3 , k4 , k6 , k9 , p, and V parameters (Table 2), which were xed at numerical values known a priori from
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HC1
A
Gempt(t) (mmolmin-1)
6 5 4 3 2 1 0 0 30 60 90
C
Gempt(t) (mmolmin-1)
6 5 4 3 2 1 0
HC2
120
150
180
210
240
30
60
90
120
150
180
210
240
Time (min)
Time (min)
B
RaG(t) (mmolmin-1)
6 5 4 3 2 1 0 -1 0 30 60 90 120 150 180 210 240
D
RaG(t) (mmolmin-1)
6 5 4 3 2 1 0 -1 0 30 60 90 120 150 180 210 240
Time (min)
Time (min)
Fig. 3 The proles of the rate of emptying of oral glucose load into the gut, Gempt (t), and the rate of glucose absorption from the gut into the mesenteric circulation, RaG (t), for the HC1-group (Panel A and B, respectively) and the HC2-group (Panel C and D, respectively) as predicted by INT M1 (dashed line) and the INT M2 (solid line). The grey area in panels B and D represents the range of variability of RaG , measured with the multiple tracer, tracer-to-tracee clamp technique during OGTT as reported by Dalla Man et al. [9].
previously reported measurements, as discussed by Brubaker et al. [4], the basal hepatic glucose balance, HGBb , and the four more glucose absorption parameters, kabs , c, b and f, were xed at numerical values taken from the literature as described in Section 2.1. Consequently, seven free parameters (k5 , k7 , k8 , M, , ke and ) characterize the INT M1 (Table 3), as well as seven are the free parameters (k5 , k7 , k8 , M, , kmin , and kmax ) that characterize the INT M2 (Table 4). Among these, the ve parameters denominated k5 , k7 , k8 , M and are the same as those dened adjustable by Brubaker et al. [4], and presumably manually adjusted in their study for qualitative representation of OGTT responses. The remaining two parameters, i.e. ke and for the INT M1 and kmin and kmax for the INT M2, are free parameters that allow individualization of the rate of ingested glucose absorption. Granted the suitability of all xed parameters, a novel aspect of the present study was the set-up of a two-step procedure that allows estimation of the free parameters of our INT M1 and INT M2 model formulations by tting to incretin, glycemia and insulinemia data taken from previously published studies [15,18], where glycemic proles observed in two groups, (HC1 and HC2) of metabolically healthy subjects, during an OGTT, were used to quantify incretin-induced insulin potentiation by comparing the insulin response to OGTT with that obtained from an isoglycemic intravenous glucose (I-IVG) infusion.
According to our two-step estimation procedure, the k7 parameter was rst estimated from tting to I-IVG insulinemia data. To this aim the Gempt (and, with it, the dynamic component of plasma incretin inow in Eq. (A14)) was set to zero and the plasma glucose compartment was fed with the glucose prole matched to that measured during OGTT (isoglycemic prole). Under these conditions the alternative formulations (M1 and M2) of glucose absorption do not come into play. This explains why both the INT M1 and the INT M2 produce the same k7 estimates and related RMSEI-IVG values, as given in Tables 3 and 4, respectively. The higher k7 estimate of 0.648 mU min1 mmol1.3 L0.3 for the HC1-group, compared to the estimate of 0.158 mU min1 mmol1.3 L0.3 for the HC2-group provides quantitative information on an enhanced insulin response to intravenous glucose infusion in the former group. This is consistent with the experimental nding of a higher value of the ratio (AUCII-IVG /AUCGI-IVG ) between the area under the curve of I-IVG suprabasal insulin to the area under the curve of the corresponding suprabasal prole of glucose infused intravenously in the HC1-group (ratio of 14.3 mU mmol1 from data of Fig. 2B and C) compared to that of the HC2-group (ratio of 5.7 mU mmol1 from data of Fig. 2E and F). Once the estimated k7 values were lled into the INT M1 and the INT M2, these two models produced a comparable
Table 3 Estimates of INT M1 model parameters in the presence of HGBb equal to 0.77 mmol min1 . k7 (CV%) mU min1 mmol1.3 L0.3
HC1 0.648 (2.2%) HC2 0.158 (2.3%)
k5 (CV%) ng L1 mmol1
6.77 (5.3%) 8.77 (2.7%)
k8 (CV%) mU min1 ng1

0.027 (4.7%) 0.017 (3.4%)
(CV%) mmol mU1

0 () 0.058 (4.9%)
M (CV%) L2 mU1 min1

0.0024 (24%) 0.0034 (5.7%)
ke (CV%) min1
0.0095 (6.9%) 0.0155 (1.1%)
(CV%)
1.0 (2.6%) 1.52 (0.8%)
RMSEI-IVG RMSEOGTT
2.96 4.16 2.21 c o m p u t e r m e t h o d s a n d p r o g r a m s i n b i o m e d i c i n e x x x ( 2 0 1 1 ) xxxxxx 3.89
HC1, group of 11 subjects with normal glucose tolerance (NGT) from Muscelli et al. [18]; HC2, group of 10 metabolically healthy subjects from Nauck et al. [15]; k7 , coefcient of appearance of insulin due to glucose, in the absence of incretin effect; k5 , gain of the zero-order transfer function between the rate of gastric emptying, Gempt , and the dynamic plasma incretin component; k8 , coefcient of appearance of insulin due to incretin; , shaping factor for derivative control of insulin on glucose; M, coefcient accounting for the effects of counter-regulatory factors on liver; ke and , fractional transfer coefcient and dimensionless shape factor of gastric emptying, respectively; CV%, precision of all parameter estimates expressed as percent coefcient of variation; RMSEI-IVG , root-mean-square error of I-IVG data t, RMSEOGTT , root-mean-square error of OGTT data t.
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Table 4 Estimates of INT M2 model parameters in the presence of HGBb equal to 0.77 mmol min1 . k7 (CV%) k5 (CV%) mU min1 mmol1.3 L0.3 ng L1 mmol1
HC1 HC2 0.648 (2.2%) 0.158 (2.3%) 5.78 (3.9%) 8.82 (2.7%)

0.025 (4.9%) 0.017 (3.3%)
(CV%) mmol mU1

0.0028 (84%) 0.0605 (4.5%)
M (CV%) L2 mU1 min1

0.0071 (5.9%) 0.0033 (5.1%)
kmin (CV%) min1

0.017 (2.6%) 0.027 (1.8%)
kmax (CV%) min1

0.038 (2.7%) 0.038 (1.4%)
RMSEI-IVG RMSEOGTT
2.96 4.16 3.90 4.07
HC1, group of 11 subjects with normal glucose tolerance (NGT) from Muscelli et al. [18]; HC2, group of 10 metabolically healthy subjects from Nauck et al. [15]; k7 , coefcient of appearance of insulin due to glucose, in the absence of incretin effect; k5 , gain of the zero-order transfer function between the rate of gastric emptying, Gempt , and the dynamic plasma incretin component; k8 , coefcient of appearance of insulin due to incretin; , shaping factor for derivative control of insulin on glucose; M, coefcient accounting for the effects of counter-regulatory factors on liver; kmin , minimum of the kempt (qsto ) function; kmax , maximum of kempt (qsto ) function; CV%, precision of all parameter estimates expressed as percent coefcient of variation; RMSEI-IVG , root-mean-square error of I-IVG data t, RMSEOGTT , root-mean-square error of OGTT data t.
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HC1, group of 11 subjects with normal glucose tolerance (NGT) from Muscelli et al. [18]; HC2, group of 10 metabolically healthy subjects from Nauck et al. [15]; 1 and 2 , respectively, quantify the rate of decrease and subsequent increase of the gastric emptying function (Eqs. (A11) and (A12), respectively); RaINCb , basal rate of appearance of incretin in the peripheral circulation (Eq. (A15)); , effects of additional regulators of I(t) on insulin appearance (Eq. (A17)); k1 and k2 are coefcients of linear glucose mediated and insulin mediated glucose uptake, respectively (Eqs. (A20) and (A21), respectively).
Table 5 Computed values of INT M1 and INT M2 model parameters.
t to incretin (closed triangles in Fig. 2A and D), glycemia (closed squares in Fig. 2B and E) and insulinemia (closed circles in Fig. 2C and F), as judged from the dashed-line proles for the INT M1 and the solid-line proles for the INT M2, and the related RMSEOGTT reported in Tables 3 and 4, respectively. Due to their ability to approximate both the OGTT and the matched I-IVG insulin response, the two models yielded estimates of the IP% index of insulin potentiation (Eq. (3)) consistent with the corresponding values computed from measured data in the HC1- and HC2-group (Table 6). The augmented insulin secretion observed after oral glucose load, compared with intravenous glucose infusion, at similar plasma glucose concentration, is attributed to the inuence of the incretin effect, most of which is due to the GLP-1 and GIP secretion [8,14,16,18,2325]. As the contribution of intestinal hormones to oral glucose-stimulated insulin secretion is relevant, and being the major stimulus to the release of these hormones clearly related to the rate of ingested glucose delivery to the gut, Gempt (t), the INC(t) signal described in Eq. (A14) by the product k5 Gempt (t) was derived from the GLP-1 and GIP responses to OGTT reported in [18] for the HC1-group and in [15] for the HC2group, respectively, by hypothesizing an additive effect as described in Section 2.2. With this assumption, the closedtriangle data of Fig. 2A and D were obtained. The lower k5 estimates provided by both the INT M1 (Table 3) and the INT M2 (Table 4) for the HC1-group, compared to those provided for the HC2-group, reect the experimental observation of a lower area under the suprabasal curve of incretin in the HC1-group (25.6 103 ng L1 over 180 min, Fig. 2A) compared to that of the HC2-group (40.0 103 ng L1 over 180 min, Fig. 2D) in response to the 75 g oral glucose challenge. On this basis, the k5 free parameter appears a suitable marker of the amplitude of the incretin response to oral glucose administration. In spite of lower incretin response, the suprabasal insulinemia response of the HC1-group, quantied by the AUCIOGTT value of 9.03 103 mU L1 over 180 min, is higher than that, 7.70 103 mU L1 over 180 min, observed in the HC2-group (compare Fig. 2C and F). This implies the presence, in the HC1group, of a compensatory increase of the insulin response to the incretin, which is reected in the increased k8 values estimated in the same group by the INT M1 (Table 3) and the INT M2 (Table 4), compared to those of the HC2-group. In the presence of this compensation, the enhanced insulin potentiation (higher IP% index; Table 6) in the HC2-group, compared to the HC1-group, is mainly explained by the observed reduction
k2 mmol mU1 min1
k1 min1
HC2 HC1 HC2 mU L1 min1 HC2 RaINCb ng min1 HC1 HC2 2 mmol1 HC1 HC2 HC1
0.024
0.040
0.024
217 217
135 135
8.66 8.41
2.22 2.21
0.0064 0.0064
0.0062 0.0062
0.0017 0.0017
HC1
0.0022 0.0022
HC2
Table 6 Insulin potentiation. IP% INT M1

HC1 HC2 63.4 81.0
1 mmol1
0.040
HC1
INT M2
62.9 81.1
EXP
63.0 78.1
HC1, group of 11 subjects with normal glucose tolerance (NGT) from Muscelli et al. [18]; HC2, group of 10 metabolically healthy subjects from Nauck et al. [15]; IP%, insulin potentiation computed by Eq. (3).
INT M1 INT M2
10
HC1 HC2 0.648 (2.2%) 0.158 (2.3%) 6.86 (5.7%) 8.85 (1.3%)

0.026 (4.8%) 0.017 (1.2%)
(CV%) mmol mU1

0 () 0.0489 (5.0%)
M (CV%) L2 mU1 min1

0 () 0.0017 (14%)
ke (CV%) min1
0.0093 (7.8%) 0.0156 (1.0%)
(CV%)
1.0 (2.9%) 1.47 (0.9%)
RMSEI-IVG
2.96 4.16
RMSEOGTT
c o m p u t e r m e t h o d s a n d p r o g r a m s i n b i o m e d i c i n e x x x ( 2 0 1 1 ) xxxxxx 2.09 4.0
See legend of Table 3 for meaning of symbols.
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HC1 HC2 0.648 (2.2%) 0.158 (2.3%) 5.95 (3.8%) 8.93 (2.7%)

0.025 (4.8%) 0.016 (3.3%)
(CV%) mmol mU1

0.0032 (65%) 0.0566 (4.9%)
M (CV%) L2 mU1 min1

0.0043 (9.1%) 0.0021 (8.0%)
kmin (CV%) min1

0.016 (2.4%) 0.026 (1.8%)
kmax (CV%) min1

0.037 (2.5%) 0.037 (1.4%)
RMSEI-IVG RMSEOGTT
2.96 4.16 3.92 4.14
See legend of Table 4 for meaning of symbols.
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4.1. Monophase vs. multiphase waveshape of gastric emptying of glucose
In conceptual terms, our INT M1 model differs from the INT M2 in that the former incorporates the hypothesis of a monophasic waveshape for the rate of gastric emptying of ingested glucose into the gut, (Gempt ; Eq. (A1) and dashed line in Fig. 3A and C), characterized by the two identiable parameters, ke and (Table 3). Instead, the INT M2 conguration assumes a three-compartment model of glucose absorption, with a nonlinear gastric emptying function (kempt ; Eq. (A10)), that yields a multiphase Gempt (solid line in Fig. 3A and C). Unfortunately, the kempt is characterized by four independent parameters (b, c, kmin and kmax ) a couple of which needs to be xed to favour numerical identiability of the INT M2 model. Our choice was, then, to x the b and c values (Table 2), which respectively locate the ex points of kempt in correspondence of the percentage of the glucose dose, D, for which the emptying function kempt (Eq. (A10)) decreases and subsequently increases at (kmax kmin )/2 [9]. The need of xing two of the four characteristic parameters of the kempt function yields a limitation in the INT M2 ability to match the data, such that no relevant benet is seen in the RMSEOGTT , compared to the INT M1 output.
of suprabasal insulin response to the OGTT-matched prole of glucose infused intravenously, as marked by a lower k7 in the HC2-group. In spite of a similar behaviour of the INT M1 and INT-M2 models in accounting for variations of k5 , k7 and k8 estimates between the HC1- and the HC2-group of healthy subjects, a relevant diversity is seen in that, in the HC1-group, the INT M1 model estimated a zero value for the and a value of M 66% lower than that produced by the INT M2. No model independent information is available to judge the reliability of estimated values for , since the small derivative dI/dt term was empirically introduced by Brubaker et al. [4] to sharpen the peak in glucose level following entry of glucose into the circulation, and was set equal to 0.06 when RaG > 0. This value is comparable with that estimated here for the HC2-group by both the INT M1 and the INT M2 (Tables 3 and 4). The zero-value estimated for by the INT M1 in the HC1 group (Table 3), as well as the corresponding very low estimate (with 84% estimation error) provided by the INT M2 (Table 4) might be ascribed to a vanishing role of the dI/dt in the presence of a limited glycemia dynamics as observed in the HC1-group compared to the HC2-group (Fig. 2B with E). Concerning the M parameter, which modulates the bilinear glucose-insulin control on hepatic balance, it is likely that its estimate is affected by the value of HGBb (Eq. (A13)) assumed as xed to favour model identiability. Because the value of 10.25 103 mmol min1 kg1 assumed here for basal hepatic glucose balance per unit BW (yielding HGBb equal to 0.77 mmol min1 for a standardized 75 kg individual), differs from the value of 12.22 103 mmol min1 kg1 (yielding HGBb equal to 0.92 mmol min1 ) previously assumed by Brubaker et al. [4], the effect of the latter HGBb value on the estimates of our free model parameters was tested. Results are given in Table 7 for the INT M1 and in Table 8 for the INT M2 model. Comparison with Tables 3 and 4, respectively, conrms that the HGBb has a major effect on the M parameter estimation. In particular, the M values of Tables 7 and 8 are signicantly underestimated with respect to the corresponding values of Tables 3 and 4. The zerovalue of M produced by the INT M1 for the HC1 group (Table 7) implies a stationary unidirectional HGB ux (Eq. (A13)), which is unlikely to occur under normal conditions [2729]. For this reason the parameter estimates obtained from our HGBb assumption (Tables 3 and 4) are more physiologically consistent. The lack of quantitative information on the HGB dynamics in humans does not allow assessment of the reliability of absolute values of M when different from zero. In describing the glucose kinetics by Eq. (A18), a linear non-insulin mediated glucose uptake, k1 G(t), was assumed here, rather than the k1 G(t)1.3 power term originally assumed by Brubaker et al. [4]. Under our simplifying assumption, which is consistent with that characterizing minimal models of glucose kinetics [1], the estimated values for the k1 coefcient (Table 5) increased in both our HC1 and HC2 groups by about 65%, compared to the k1 values computed in the presence of the k1 G(t)1.3 power term. Practically no effect was observed in the RMSEOGTT of data t and in the estimates of free model parameters.
4.2.
Summary and conclusions
An improvement over a mathematical model previously proposed by Brubaker et al. [4] to simulate the glycemia and insulinemia responses to an OGTT, was accomplished here by replacing the previously proposed empirical description of glucose absorption, restricted to 50 and 100 g glucose challenge, with either the M1 and the M2 model congurations depicted in Fig. 1 and mathematically described in the Appendix A. This new arrangement, gave rise to our INT M1 and INT M2 integrated models, respectively, that allow a reliable description of glycemic and insulinemic responses to a clinically consistent 75 g OGTT. Under the hypothesis of an additive effect of GLP-1 and GIP on insulin potentiation, our results showed a substantial equivalence of the two alternative INT M1 and INT M2 models in reproducing insulin potentiation as observed by comparing mean OGTT responses to a 75 g oral glucose challenge with matched I-IVG responses, as reported in [18] and in [15] for two different groups of healthy subjects, here denominated HC1 and HC2, respectively. Especially, the implementation of both the INT M1 and INT M2 models in our two-step parameter estimation procedure allowed assessment of k5 , k7 and k8 parameters, which appear as suitable markers of the differences in the incretin, glucose and insulin responses between the two groups. Namely, k5 is a marker of the amplitude of the incretin response to oral glucose administration; k8 is a marker of the insulin response to the incretin, while k7 is a marker of the insulin response irrespective of incretin effect. A higher k8 value estimated by both the INT M1 and the INT M2 in the HC1-group, compared to the HC2, indicates the presence, in the former group of an increase of insulin response to incretin, which compensates for a lower incretin response to oral glucose load (lower k5 in the HC1). In the presence of this compensation, the enhanced insulin potentiation
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(higher IP% index; Table 6) in the HC2-group, compared to the HC1-group, is mainly explained by the observed reduction of suprabasal insulin response to the OGTT-matched prole of glucose infused intravenously, as marked by a lower k7 in the HC2-group. Owing to the substantial equivalence of INT M1 and INTM2 behaviour, the former model appears the best compromise between simplicity and predictive capability. Model implementation in our two-step parameter estimation procedure enhances the possibility of a prospective application for individualization of the incretin effect in a single subject, when his/her data are plugged in.
with the initial conditions being the basal values qsto1b , qsto2b and qgutb reported in Table 1. In these equations (t) is the impulse function, D (mmol) is the amount of ingested glucose, k21 (min1 ) is the rate of grinding, Gempt (mmol min1 ) is the rate of emptying of the oral glucose load into the gut, RaG (mmol min1 ) is the rate of glucose absorption from the gut into the mesenteric circulation; kabs (min1 ) is the rate constant of intestinal absorption, f is the fraction of the intestinal absorption which actually appears in the plasma, and kempt (min1 ) is a gastric emptying function, which depends on the total amount of glucose in the stomach, qsto (mmol), as follows [9]: kempt (qsto ) = kmin + kmax kmin {tanh[1 (qsto b D)] 2 (A10)
Appendix A. Mathematical formulation of our 75 g OGTT integrated models

A.1. M1 model of oral glucose absorption
This model describes glucose absorption by the gut as shown in the M1 panel of Fig. 1. Under the assumption that, after ingestion of a glucose dose, D (75 g, equivalent to 417 mmol), the fraction of glucose in the duodenum follows a power exponential function increase, the rate of emptying of the oral glucose load into the gut, Gempt (mmol min1 ), is described by the following equation [7,9]: Gempt (t) = D ke t1 e[(ke t)
tanh[2 (qsto c D)] + 2}
As reported by Dalla Man et al. [9], this model is suitable to describe glucose absorption during an OGTT under the assumption of kempt = kmax at qsto = D (full stomach) and at qsto = 0 (empty stomach). This assumption yields the following expressions for the 1 and 2 parameters: 1 = 5 2 D (1 b) 5 2Dc (A11)
(A1)
2 =
(A12)
where ke (min1 ) is a fractional transfer coefcient and a dimensionless shape factor. Denoting the amount of glucose in the gut as qgut (mmol), the rate constant of intestinal absorption as kabs (min1 ), the fraction of the intestinal absorption which actually appears in plasma as f, and the rate of appearance of ingested glucose into plasma as RaG (mmol min1 ), the following equations hold [7,9]: qgut (t) = kabs qgut (t) + Gempt (t) RaG (t) = f kabs qgut (t) (A2) (A3)
A.3. Hepatic glucose balance

Hepatic glucose balance (HGB; mmol min1 ) represents the net ux of glucose G (mmol L1 ) across the hepatic bed, thereby reecting the sum of glucose production and glucose uptake from the mesenteric circulation (e.g., following the oral glucose load). In accordance with Brubaker et al. [4] the following equation is assumed to describe the HGB(t) dynamics in healthy conditions: HGB(t) = HGBb + M [Gb G(t)] I(t) (A13)
A.2. M2 model of oral glucose absorption

The representation of glucose absorption displayed in the M2 panel of Fig. 1 assumes two compartments (qsto1 and qsto2 , respectively) for the stomach, and a single compartment, qgut , for the intestine. Mathematical description is as follows [9]: qsto1 (t) = k21 qsto1 (t) + D (t) qsto2 (t) = kempt (qsto ) qsto2 (t) + k21 qsto1 (t) qgut (t) = kabs qgut (t) + kempt (qsto ) qsto2 (t) qsto (t) = qsto1 (t) + qsto2 (t) Gempt (t) = kempt (qsto ) qsto2 (t) RaG (t) = f kabs qgut (t) (A4) (A5) (A6) (A7) (A8) (A9)
In this equation, HGBb is basal hepatic glucose balance, Gb is basal glucose concentration, while G(t) and I(t) represent the time course of glucose and insulin concentrations. M is a modulating factor in the bilinear control term.
A.4. Incretin response

The following differential equation was assumed to describe the kinetics of the incretin [4]: RaINCb dINC(t) = + k5 Gempt (t) k6 INC(t) dt V (A14)
According to this equation, three terms determine the rate of variation with time of circulating incretin concentrations (INC), based on the combined contribution of glucagonlike peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) [8,14,16,18,2325]. The rst term is the basal rate of appearance of the incretin (RaINCb ; ng min1 ),
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to insulin mediated glucose uptake, and assuming a value of 2 for basal conditions [31,32], the following relation holds: p= k1 Gb =2 k2 Ib (A19)
normalized to distribution volume (V); the second term is proportional, through the k5 constant (ng L1 mmol1 ), to the prole of the rate of gastric emptying into the gut (Gempt ; mmol min1 ); and, eventually the third term accounts for a negative contribution, proportional through the k6 (min1 ) to the time course of the incretin (INC; ng L1 ) due to the removal of bioactive GIP and GLP-1 from the circulation [30]. The quantity RaINCb = k6 V INCb (A15)
From Eq. (A18) written for steady state conditions (dG/dt = 0 and dI/dt = 0) and Eq. (A19), the values of the constants k1 (min1 ) and k2 (mmol min1 mU1 ) are given by the following equations [4]: k1 = HGBb p p+1 Gb V 1 HGBb p+1 Ib V (A20)
is obtained from Eq. (A14) by setting the derivative equal to zero, which occurs when Gempt equals zero.
k2 =
(A21)
A.5. Insulin response

The following differential equation was assumed to describe insulin kinetics [4]: dI(t) 1.3 = k7 G(t) + k8 INC(t) k9 I(t) + dt As reported by Brubaker et al. [4], the Eq. (A18) works well under normoglycemic conditions. To account for urinary glucose loss during hyperglycemia (G > 10 mmol L1 ), an additional term is added as shown in the following equation: RaG (t) HGB(t) dG(t) = + k1 G(t) k2 I(t) + dt V V dI(t) k3 G(t) k4 dt V (A22)
(A16)
Eq. (A16) is based on the assumption that four terms determine the rate of variation with time of circulating insulin. The rst nonlinear term, assumed equal to k7 G(t)1.3 , accelerates the effect of plasma glucose on insulin release, with respect to a linear term; the second and the third terms are proportional, through the k8 (mU min1 ng1 ) and k9 (min1 ) constants, respectively, to the circulating concentrations of the incretin and insulin; and eventually, the constant term, (mU L1 min1 ), which is expressed, in steady state, in terms of the known basal values of G and I, after setting the derivative term, dI/dt, equal to zero and solving for : = k9 Ib k8 INCb k7 G1.3 b (A17)
references
A.6. Plasma glucose kinetics

The following differential equation was assumed to describe the glucose kinetics [4]: RaG (t) HGB(t) dG(t) = + k1 G(t) k2 I(t) + dt V V dI(t) dt (A18)
According to this equation, the rate of change of glucose concentration during an OGTT depends on glucose absorption from the gut into the mesenteric circulation (RaG (t)/V); net absorption/production of glucose by the liver (HGB(t)/V); insulin mediated glucose uptake, k2 I(t); and a small corrective term, dI(t)/dt, which has the effect of sharpening the peak in glucose level following entry of glucose into the circulation. A linear, k1 G(t), non-insulin mediated glucose uptake was assumed here, rather than the k1 G(t)1.3 power term originally assumed by Brubaker et al. [4]. Under these assumptions, denoting as p the ratio of non-insulin mediated
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COMM-3248; No.

journal homepage: www.intl.elsevierhealth.com/journals/cmpb

COMM-3248; No. of Pages 14

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Model testing vs. reported experimental data

Parameter estimation procedure

L min1 mmol min1 min1 min1 L

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AUCIOGTT AUCII-IVG 100 AUCIOGTT

INCm (ti ) INC(ti )

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k8 (CV%) mU min1 ng1

(CV%) mmol mU1

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kmax (CV%) min1

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Table 5 Computed values of INT M1 and INT M2 model parameters.

k2 mmol mU1 min1

Table 6 Insulin potentiation. IP% INT M1

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k8 (CV%) mU min1 ng1

(CV%) mmol mU1

M (CV%) L2 mU1 min1

See legend of Table 3 for meaning of symbols.

k8 (CV%) mU min1 ng1

(CV%) mmol mU1

M (CV%) L2 mU1 min1

kmin (CV%) min1

kmax (CV%) min1

See legend of Table 4 for meaning of symbols.

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Summary and conclusions

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Appendix A. Mathematical formulation of our 75 g OGTT integrated models

tanh[2 (qsto c D)] + 2}

A.3. Hepatic glucose balance

A.2. M2 model of oral glucose absorption

A.4. Incretin response

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A.5. Insulin response

A.6. Plasma glucose kinetics

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